Patent Publication Number: US-2022233708-A1

Title: Antibody-drug conjugate, intermediate thereof, preparation method therefor and application thereof

Description:
The present application claims the priority of the Chinese patent application CN2019105779096 filed on Jun. 28, 2019. The entire disclosure of the above Chinese patent application is incorporated herein by reference in its entireties. 
     TECHNICAL FIELD 
     The present disclosure relates to a field of biotechnology and medicine, especially relates to an antibody drug conjugate, an intermediate thereof, a preparation method therefor and an application thereof. 
     BACKGROUND 
     Antibody drug conjugate (ADC) has been one of the hot spots in the pharmaceutical industry in recent years. Due to the unsatisfactory clinical efficacy of many antibody drugs, many industry giants are increasingly turning their attention to ADC drugs. At present, seven ADC drugs have been approved for sale abroad. On May 17, 2000, the FDA approved the listing of Pfizer&#39;s Gemtuzumab Ozogamicin (trade name Mylotarg) for the treatment of acute myeloid leukemia (AML) patients who have relapsed for the first time, are over 60 years old, are CD33+, and are not suitable for cytotoxic chemotherapy. Gemtuzumab Ozogamicin was withdrawn from the market in 2010 but re-listed in 2017. In the same year, Pfizer&#39;s Inotuzumab ozogamicin (trade name Besponsa) was also approved by the FDA for the treatment of adult relapsed and refractory B-cell ALL. On Aug. 19, 2011, the FDA approved the listing of Brentuximab Vedotin (trade name Adcetris) developed by Seattle Genetics for the treatment of CD30-positive Hodgkin&#39;s lymphoma (HL) and rare disease systemic anaplastic large cell lymphoma (SALCL). On Feb. 22, 2013, the ado-trastuzumab emtansine (T-DM1, trade name Kadcyla) developed by Genentech was approved for sale by the FDA and is mainly used for the treatment of Her2-positive advanced (metastatic) breast cancer. Especially in 2019, polatuzumab vedotin (trade name Polivy), enfortumab vedotin (trade name Padcev) and fam-trastuzumabderuxtecan (trade name Enhertu) were approved for sale subsequently. In addition, there are more than 100 ADC drugs in the clinical and pre-clinical development stage internationally. 
     The basic modules of antibody drug conjugate include antibody, linker, and effector molecule. The antibody is used to transfer effector molecule to the tumor for enrichment, thereby killing tumor cells. Traditional effector molecules are mostly high-activity tubulin inhibitors, which usually have relatively large toxic and side effects, which limits the application of ADCs. Recently, Immunomedics company invented a new type of ADC drug IMMU-132 (ZL200980156218) with camptothecin compound as the effector molecule, which showed good anti-tumor effect. Daiichi Sankyo invented another ADC drug DS-8201a (ZL201380053256) with camptothecin compound as the effector molecule, which also showed good anti-tumor effects. In existing ADC technology, the linker used to connect the camptothecin compound and the antibody is seldom studied. Generally speaking, the ideal linker in ADC needs to meet the following requirements: first, ensure that the small molecule drug is not separated from the antibody in the plasma, after entering the cell, the linker will be broken under appropriate conditions to quickly release the active small molecule drug; secondly, the linker must have good physical and chemical properties so that it can be connected to the antibody to form a conjugate; and, the linker must be easy to prepare to lay the foundation for the large-scale production of ADC. IMMU-132 uses a pH-sensitive linker, which has poor stability. DS-8201a uses a tetrapeptide structure containing glycine-glycine-phenylalanine-glycine, compared with the general cathepsin B substrate sequence (such as valine-citrulline), the enzyme cleavage reaction is slow and there is poor physical and chemical properties and difficulty in synthesis. 
     Content of the Present Invention 
     The technical problem to be solved in the present disclosure is for overcoming the defect of a single type of the existing antibody drug conjugate, and provide an antibody drug conjugate, an intermediate thereof, a preparation method therefor and an application thereof. The antibody drug conjugate can realize the wide application of cytotoxic drugs in the field of ADCs, and treat tumor patients who are resistant to microtubule ADCs. 
     The present disclosure provides antibody drug conjugates with a variety of specific structural linkers, the antibody drug conjugates inhibit the growth of mammalian tumors and can be used to treat a variety of cancers. The antibody drug conjugates have better biological activity, stability and uniformity, have reduced toxic and side effects, and faster release rate of enzyme cleavage in tumor cells. 
     The present disclosure solves the above technical problems through the following technical solutions: 
     The present disclosure provides an antibody drug conjugate, a general structural formula of the antibody drug conjugate is Ab-(L 3 -L 2 -L 1 -D) m ; 
     wherein, Ab is an antibody; 
     D is a cytotoxic drug; 
     m is 2-8; 
     the structure of L 1  is as shown in formula I, II, III or IV, a-end of the L 1  is connected to the cytotoxic drug, and e-end of the L 1  is connected to c-end of the L 2 ; 
     
       
         
         
             
             
         
       
     
     wherein L is independently phenylalanine residue, alanine residue, glycine residue, glutamic acid residue, aspartic acid residue, cysteine residue, histidine residue, isoleucine residue, leucine residue, lysine residue, methionine residue, proline residue, serine residue, threonine residue, tryptophan residue, tyrosine residue or valine residue; p is 2-4; 
     R 1  is C 1 -C 6  alkyl substituted by C 1 -C 6  alkyl substituted by R 1-3  S(O) 2 —, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl or 5 to 14-membered heteroaryl; the heteroatoms in the 5 to 14-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, or 4; 
     the R 1-1 , R 1-2  and R 1-3  are independently C 1 -C 6  alkyl; 
     L 2  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein n is independently 1-12, c-end of the L 2  is connected to e-end of the L 1 , f-end of the L 2  is connected to d-end of the L 3 ; 
     L 3  is 
     
       
         
         
             
             
         
       
     
     wherein b-end of the L 3  is connected to the Ab, d-end of the L 3  is connected to f-end of the L 2 ; 
     when the structure of the L 1  is as shown in formula I, the L 3  is 
     
       
         
         
             
             
         
       
     
     the L 2  is not 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, in the antibody drug conjugates, some groups have the following definitions, and the definitions of unmentioned groups are as described in any of the above solutions (content of this paragraph is hereinafter referred to as “in a preferred embodiment of the present disclosure”): 
     the antibody can be a conventional antibody in the field of anti-tumor ADCs, preferably anti-HER2 antibody Trastuzumab or variant thereof, anti-B7-H3 antibody P2E5 or variant thereof, anti-Claudin18.2 antibody IMAB362 or variant thereof, or anti-Trop2 antibody RS7 or variant thereof, further preferably anti-HER2 antibody Trastuzumab or variant thereof, anti-B7-H3 antibody P2E5 or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof, further more preferably anti-HER2 antibody Trastuzumab or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof, and most preferably anti-HER2 antibody Trastuzumab or anti-Claudin 18.2 antibody IMAB362. The amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing. The amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing. The amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. The amino acid sequence of the light chain in the anti-Trop2 antibody RS7 is preferably shown in SEQ ID No. 3 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Trop2 antibody RS7 is preferably shown in SEQ ID No. 4 in the sequence listing. The anti-HER2 antibody Trastuzumab variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology compared with the anti-HER2 antibody Trastuzumab. The anti-B7-H3 antibody P2E5 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology compared with the anti-B7-H3 antibody P2E5. The anti-Trop2 antibody RS7 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology compared with the anti-Trop2 antibody RS7. The anti-Claudin 18.2 antibody IMAB362 variant has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology compared with the anti-Claudin 18.2 antibody IMAB362. 
     In a preferred embodiment of the present disclosure, b-end of the L 3  is preferably connected to the sulfhydryl in the antibody in the form of a thioether bond. Taking 
     
       
         
         
             
             
         
       
     
     as an example, the connection form of 
     
       
         
         
             
             
         
       
     
     to the cysteine residue in the antibody is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the cytotoxic drug can be a conventional cytotoxic drug in the field of ADCs, particularly preferably a topoisomerase inhibitor containing a hydroxyl group, and more preferably a topoisomerase I inhibitor containing a hydroxyl group, further preferably camptothecin or derivatives thereof, and further more preferably 
     
       
         
         
             
             
         
       
     
     The L 1  is preferably connected to the hydroxyl group in the cytotoxic drug in the form of an ether bond. After the L 1  is connected to 
     
       
         
         
             
             
         
       
     
     the fragment of the cytotoxic drug remaining in the antibody drug conjugate is preferably 
     
       
         
         
             
             
         
       
     
     Taking 
     
       
         
         
             
             
         
       
     
     as examples, the -L 1 -D can be 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , the the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably ethyl. The R 1-1  and R 1-2  are each independently preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably ethyl. The R 1-3  is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl; the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl or ethyl. 
     In a preferred embodiment of the present disclosure, the m is preferably 4-8, more preferably 7-8 (for example, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 8.0). 
     In a preferred embodiment of the present disclosure, the L is preferably valine residue or alanine residue, and p is preferably 2. The (L)p is further preferably 
     
       
         
         
             
             
         
       
     
     wherein the amino-end of the (L)p is connected to the carbonyl-end in the formula III. 
     In a preferred embodiment of the present disclosure, the n is preferably 8-12 (for example, 8 and 12). 
     In a preferred embodiment of the present disclosure, the R 1-1 , R 1-2  and R 1-3  are independently preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, the R 1  is preferably C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 6  alkyl, more preferably C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2  or C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, most preferably C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —. When R 1  is C 1 -C 6  alkyl, the C 1 -C 6  alkyl is preferably methyl or ethyl. The C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 — is preferably 
     
       
         
         
             
             
         
       
     
     The C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the 
     
       
         
         
             
             
         
       
     
     is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula I, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula II, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula IV, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the structure of L 1  is preferably as shown in formula I or III. 
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula I, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula I, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, L 2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, L 2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, L 1  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, in the antibody-drug conjugate, the Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof; the D is a cytotoxic drug; the m is 2-8; 
     the structure of the L 1  is as shown in formula I, II, III or IV, 
     
       
         
         
             
             
         
       
     
     the L 2  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     the n is independently 8-12; 
     the L 3  is 
     
       
         
         
             
             
         
       
     
     the L is independently valine residue or alanine residue; the p is 2 to 4; 
     the R 1  is C 1 -C 6  alkyl substituted by C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 6  alkyl; 
     the R 1-1- , R 1-2  and R 1-3  are each independently C 1 -C 6  alkyl; 
     wherein, the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, in the antibody drug conjugate, the Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof; the D is 
     
       
         
         
             
             
         
       
     
     the m is 7-8; 
     the structure of the L 1  is as shown in formula I or III, 
     
       
         
         
             
             
         
       
     
     when the structure of the L 1  is as shown in formula I, the L 2  is 
     
       
         
         
             
             
         
       
     
     the n is independently 8-12; 
     when the structure of the L 1  is as shown in formula III, the L 2  is 
     
       
         
         
             
             
         
       
     
     the n is independently 8-12; 
     the L 3  is 
     
       
         
         
             
             
         
       
     
     the L is independently valine residue or alanine residue; the p is 2 to 4; 
     the R 1  is C 1 -C 4  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 4  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 4  alkyl; the R 1 , R 1-2  and R 1-3  are independently C 1 -C 4  alkyl; 
     the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, wherein Ab is antibody; D is 
     
       
         
         
             
             
         
       
     
     L 1  is 
     
       
         
         
             
             
         
       
     
     wherein, L is valine residue or alanine residue, p is 2, (L)p is preferably 
     
       
         
         
             
             
         
       
     
     R 1  is C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 6  alkyl, preferably C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2  or C 1 -C 6  alkyl substituted by R 1-3  S(O) 2 —, more preferably C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —; the R 1-1 , R 1-2  and R 1-3  are independently C 1 -C 4  alkyl, preferably methyl; the C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2  is preferably 
     
       
         
         
             
             
         
       
     
     the C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 — is preferably 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
     
     wherein, n is preferably 8; L 2  is preferably 
     
       
         
         
             
             
         
       
     
     L 3  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the structure of the L 1  is as shown in formula III, the L 2  is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, m is 2-8, preferably 7-8, for example 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0; 
     Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or anti-Claudin 18.2 antibody IMAB362; the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 6 in the sequence listing; wherein, m is 2-8, preferably 7-8, for example 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     preferably 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 6 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 6 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-B7-H3 antibody P2E5; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 8 in the sequence listing, wherein, m is 2-8, preferably 7-8, for example 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-B7-H3 antibody P2E5; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 8 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-Claudin18.2 antibody IMAB362; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 2 in the sequence listing; wherein, m is 2-8, preferably 7-8, for example 7.3, 7.4, 7.5, 7.6, 7.7, 7.8 or 8.0. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-Claudin18.2 antibody IMAB362; or, the amino acid sequence of the light chain in the Ab is shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the Ab is shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
     
     wherein, Ab, m and R 1  are as defined above. 
     The present disclosure also provides a linker-drug conjugate, a general structural formula of the linker-drug conjugate is L 4 -L 2 -L 1 -D; wherein L 4  is 
     
       
         
         
             
             
         
       
     
     L 2 , L 1 , and D are as defined above, f-end of the L 2  is connected to d-end of the L 4 ; when the L 4  is 
     
       
         
         
             
             
         
       
     
     when the L 1  is 
     
       
         
         
             
             
         
       
     
     the L 2  is not 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the linker-drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
     
     wherein, R 1  is as defined above. 
     In a preferred embodiment of the present disclosure, the linker-drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The present disclosure also provides a compound as follows, 
     
       
         
         
             
             
         
       
     
     wherein, R 1  is as defined above; 
     R 2  is —N 3 , —NH 2 , 
     
       
         
         
             
             
         
       
     
     The present disclosure also provides the compounds as follows, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The present disclosure provides an antibody drug conjugate, a general structural formula of the antibody drug conjugate is Ab-(L 3 -L 2 -L 1 -D) m ; 
     wherein, Ab is an antibody; 
     D is a cytotoxic drug; 
     m is 2-8; 
     the structure of L 1  is as shown in formula I, II, III or IV, a-end of the L 1  is connected to the cytotoxic drug, and e-end of the L 1  is connected to c-end of the L 2 ; 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein n is independently 1-12, c-end of the L 2  is connected to e-end of the L 1 , f-end of the L 2  is connected to d-end of the L 3 ; 
     L 3  is 
     
       
         
         
             
             
         
       
     
     wherein b-end of the L 3  is connected to the Ab, d-end of the L 3  is connected to f-end of the L 2 ; 
     wherein L is independently phenylalanine residue, glycine residue, glutamic acid residue, aspartic acid residue, cysteine residue, histidine residue, isoleucine residue, leucine residue, lysine residue, methionine residue, proline residue, serine residue, threonine residue, tryptophan residue, tyrosine residue or valine residue; p is 2-4; 
     R 1  is C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by R 1-3  S(O) 2 —, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl or 5 to 14-membered heteroaryl; the heteroatoms in the 5 to 14-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, or 4; 
     the R 1-1 , R 1-2  and R 1-3  are independently C 1 -C 6  alkyl; 
     when the structure of the L 1  is as shown in formula I, the L 3  is 
     
       
         
         
             
             
         
       
     
     the L 2  is not 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, in the antibody drug conjugates, some groups have the following definitions, and the definitions of unmentioned groups are as described in any of the above solutions (content of this paragraph is hereinafter referred to as “in a preferred embodiment of the present disclosure”): 
     the antibody can be a conventional antibody in the field of anti-tumor ADCs, preferably anti-HER2 antibody Trastuzumab or variant thereof, anti-B7-H3 antibody P2E5 or variant thereof, anti-Claudin18.2 antibody IMAB362 or variant thereof, or anti-Trop2 antibody RS7 or variant thereof, further preferably anti-HER2 antibody Trastuzumab or variant thereof, anti-B7-H3 antibody P2E5 or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof, further more preferably anti-HER2 antibody Trastuzumab or variant thereof, or anti-Claudin 18.2 antibody IMAB362 or variant thereof, and most preferably anti-HER2 antibody Trastuzumab or anti-Claudin 18.2 antibody IMAB362. The amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing. The amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing. The amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. The amino acid sequence of the light chain in the anti-Trop2 antibody RS7 is preferably shown in SEQ ID No. 3 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Trop2 antibody RS7 is preferably shown in SEQ ID No. 4 in the sequence listing. 
     In a preferred embodiment of the present disclosure, b-end of the L 3  is preferably connected to the sulfhydryl in the antibody in the form of a thioether bond. Taking 
     
       
         
         
             
             
         
       
     
     as an example, the connection form of 
     
       
         
         
             
             
         
       
     
     to the cysteine residue in the antibody is 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the cytotoxic drug can be a conventional cytotoxic drug in the field of ADCs, particularly preferably a topoisomerase inhibitor containing a hydroxyl group, and more preferably a topoisomerase I inhibitor containing a hydroxyl group, further preferably camptothecin or derivatives thereof, and further more preferably 
     
       
         
         
             
             
         
       
     
     The L 1  is preferably connected to the hydroxyl group in the cytotoxic drug in the form of an ether bond. After the L 1  is connected to 
     
       
         
         
             
             
         
       
     
     the fragment of the cytotoxic drug remaining in the antibody drug conjugate is preferably 
     
       
         
         
             
             
         
       
     
     Taking 
     
       
         
         
             
             
         
       
     
     as examples, the -L 1 -D can be 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl 1-1-12, substituted by —NR 1-1 R 1-2 , the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably ethyl. The R″ and R 1-2  are each independently preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably ethyl. The R 1-3  is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, when the R 1  is C 1 -C 6  alkyl, the C 1 -C 6  alkyl is preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, the m is preferably 4-8, more preferably 7-8 (for example, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8). 
     In a preferred embodiment of the present disclosure, the L is preferably valine residue or alanine residue, and p is preferably 2. The (L)p is further preferably 
     
       
         
         
             
             
         
       
     
     wherein the amino-end of the (L) p  is connected to the carbonyl-end in the formula III. 
     In a preferred embodiment of the present disclosure, the n is preferably 8-12 (for example, 8 and 12). 
     In a preferred embodiment of the present disclosure, the R 1-1 , R 1-2  and R 1-3  are independently preferably C 1 -C 4  alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 
     In a preferred embodiment of the present disclosure, the 
     
       
         
         
             
             
         
       
     
     is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula I, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula II, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula III, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     In a preferred embodiment of the present disclosure, when the structure of L 1  is as shown in formula IV, the L 2  is preferably 
     
       
         
         
             
             
         
       
     
     the L 3  is preferably 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the R 1  is preferably C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 6  alkyl. 
     In a preferred embodiment of the present disclosure, in the antibody drug conjugate, the Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or variant thereof, anti-Claudin18.2 antibody IMAB362 or variant thereof; the D is a cytotoxic drug; the m is 2-8; 
     the structure of the L 1  is as shown in formula I, II, III or IV, 
     
       
         
         
             
             
         
       
     
     the L 2  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     the n is independently 8-12; 
     the L 3  is 
     
       
         
         
             
             
         
       
     
     the L is independently valine residue or alanine residue; the p is 2-4; 
     the R 1  is C 1 -C 6  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by R 1-3  S(O) 2 —, or C 1 -C 6  alkyl; 
     the R 1-1 , R 1-2  and R 1-3  are independently C 1 -C 6  alkyl; 
     wherein, the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, in the antibody drug conjugate, the Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or variant thereof, anti-Claudin18.2 antibody IMAB362 or variant thereof; the D is 
     
       
         
         
             
             
         
       
     
     the m is 7-8; 
     when the structure of L 1  is as shown in formula I, the L 2  is 
     
       
         
         
             
             
         
       
     
     the n is independently 8-12; 
     when the structure of L 1  is as shown in formula II, the L 2  is 
     
       
         
         
             
             
         
       
     
     the n is 8-12; 
     when the structure of L 1  is as shown in formula III, the L 2  is 
     
       
         
         
             
             
         
       
     
     then is 8-12; 
     when the structure of L 1  is as shown in formula IV, the L 2  is 
     
       
         
         
             
             
         
       
     
     the L 3  is 
     
       
         
         
             
             
         
       
     
     the L is independently valine residue or alanine residue; the p is 2 to 4; 
     the R 1  is C 1 -C 4  alkyl substituted by —NR 1-1 R 1-2 , C 1 -C 4  alkyl substituted by R 1-3 S(O) 2 —, or C 1 -C 4  alkyl; the R 1-1 , R 1-2  and R 1-3  are independently C 1 -C 4  alkyl; 
     the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab, anti-B7-H3 antibody P2E5 or anti-Claudin 18.2 antibody IMAB362, m is 7.3, 7.4, 7.5, 7.6, 7.7 or 7.8; the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is preferably shown in SEQ ID No. 2 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     preferably 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab; the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
     
     wherein, Ab is anti-HER2 antibody Trastuzumab; the amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is preferably shown in SEQ ID No. 6 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-B7-H3 antibody P2E5; the amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is preferably shown in SEQ ID No. 8 in the sequence listing. 
     In a preferred embodiment of the present disclosure, the antibody drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, Ab is anti-Claudin 18.2 antibody IMAB362; the amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 2 in the sequence listing. 
     The present disclosure also provides a linker-drug conjugate, a general structural formula of the linker-drug conjugate is L 4 -L 2 -L 1 -D; wherein L 4  is 
     
       
         
         
             
             
         
       
     
     L 2 , L 1 , and D are as defined above, f-end of the L 2  is connected to d-end of the L 4 ; when the L 4  is 
     
       
         
         
             
             
         
       
     
     the L 1  is 
     
       
         
         
             
             
         
       
     
     the L 2  is not 
     
       
         
         
             
             
         
       
     
     In a preferred embodiment of the present disclosure, the linker-drug conjugate is preferably any of the compounds shown below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The present disclosure also provides compounds as follows, 
     
       
         
         
             
             
         
       
     
     The present disclosure provides a method for preparing the antibody drug conjugate, comprising the following steps, coupling the linker-drug conjugate with the antibody. 
     In the present disclosure, the coupling conditions and operations can be conventional conditions and operations for coupling in the art. 
     The present disclosure also provides a pharmaceutical composition, comprising the antibody drug conjugate and a pharmaceutically acceptable carrier. 
     The present disclosure also provides a use of the antibody drug conjugate or the pharmaceutical composition in the preparation of a medicament for the prevention or treatment of a cancer. The cancer is preferably gastric cancer, breast cancer, non-small cell lung cancer, urothelial cancer or pancreatic cancer. 
     The present disclosure also provides a method for the prevention and/or treatment of a cancer, comprising administrating a therapeutically effective amount of the antibody drug conjugate or the pharmaceutical composition to a subject. The cancer is preferably gastric cancer, breast cancer, non-small cell lung cancer, urothelial cancer or pancreatic cancer. 
     In the present disclosure, m represents the molar ratio of cytotoxic drug molecule to Ab (also known as DAR, that is, drug antibody coupling ratio), m can be an integer or a decimal, and is preferably understood as: the average value of the molar ratio of the drug molecule to the monoclonal antibody molecule in the antibody drug conjugate obtained by coupling a single monoclonal antibody molecule with cytotoxic drug, generally can be measured by Hydrophobic-Interaction Chromatography (HIC), polyacrylamide-SDS gel electrophoresis (SDS-PAGE, electrophoresis), liquid chromatograph-mass spectrometer (LC-MS) and other methods. 
     In the present disclosure, the term “C 1 -C 6  alkyl” alone or in combination represents a saturated linear or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, such as methyl and ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably “C 1 -C 6  alkyl” represents methyl or ethyl. 
     The antibody of the present disclosure can be prepared by well-known techniques in the art, such as hybridoma methods, recombinant DNA techniques, phage display techniques, synthesis techniques, or a combination of these techniques, or other techniques known in the art. 
     Variants refer to mutants of the amino acid sequence of antibody and covalent derivatives of natural polypeptides, provided that the biological activity equivalent to that of natural polypeptides is retained. The difference between amino acid sequence mutants and natural amino acid sequences is generally that one or more amino acids in the natural amino acid sequence are replaced or one or more amino acids are deleted and/or inserted in the polypeptide sequence. Deletion mutants include fragments of natural polypeptides and N-terminal and/or C-terminal truncation mutants. Generally, amino acid sequence mutants have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology compared with natural sequence. 
     The term “treatment” or its equivalent expression when applied to, for example, cancer, refers to a procedure or process used to reduce or eliminate the number of cancer cells in a patient or alleviate the symptoms of cancer. “Treatment” of cancer or other proliferative disorders does not necessarily mean that cancer cells or other disorders will actually be eliminated, the number of cells or disorders will actually be reduced or the symptoms of cancer or other disorders will actually be alleviated. Normally, even if there is only a low probability of success, the method of treating cancer will be performed, but the patient&#39;s medical history and estimated survival expectations are taken into account, it is still considered to induce an overall beneficial course of action. 
     The term “pharmaceutically acceptable carrier” refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the art of cosmetics or topical medicine. 
     On the basis of not violating common knowledge in the art, the preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present disclosure. 
     The reagents and raw materials used in the present disclosure are all commercially available. 
     The positive and progressive effect of the present disclosure is that: the antibody drug conjugate of the present disclosure has better biological activity, stability and uniformity, has reduced toxic and side effects, and has a faster release rate of enzyme cleavage in tumor cells. The use of this new type of antibody drug conjugate can achieve the widely use of cytotoxic drugs, especially camptothecin compounds in the field of ADCs, and treat tumor patients who are resistant to microtubule ADCs. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
       
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Description of abbreviations 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 SMCC 
                 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid 
               
               
                   
                   
                 succinimidyl ester 
               
               
                   
                 DMF 
                 N,N-Dimethylformamide 
               
               
                   
                 ESI-MS 
                 Electrospray mass spectrometry 
               
               
                   
                 HATU 
                 2-(7-Azabenzotriazol-1-yl )-N,N,N′,N′- 
               
               
                   
                   
                 tetramethyluronium hexafluorophosphate 
               
               
                   
                 TCEP 
                 Tris(2-carboxyethyl)phosphine 
               
               
                   
                 DMSO 
                 Dimethyl sulfoxide 
               
               
                   
                 UV 
                 Ultraviolet visible light 
               
               
                   
                 v/v 
                 Volume ratio 
               
               
                   
                 mmol 
                 Millimole 
               
               
                   
                 h 
                 Hour 
               
               
                   
                 g 
                 Gram 
               
               
                   
                 IC 50   
                 Half inhibitory concentration 
               
               
                   
                 PB 
                 Phosphate buffer 
               
               
                   
                 EDTA 
                 Ethylenediaminetetraacetic acid 
               
               
                   
                 MMT 
                 4-Methoxytrityl 
               
               
                   
                   
               
            
           
         
       
     
     The following embodiments further illustrate the present disclosure, but the present disclosure is not limited thereto. In the following embodiments, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification. 
     Embodiment 1: Synthesis of LE 01 
     
       
         
         
             
             
         
       
     
     Commercially available SMCC (1 mmol, 0.32 g) and compound A (0.5 mmol, 0.42 g) were dissolved in 10 mL of DMF, the mixture was stirred at room temperature for 3 h, and the solvent was removed by distillation under reduced pressure, the crude product was purified by silica gel column chromatography [chloroform-chloroform:methanol=9:1 (V/V)] to obtain the title compound (0.5 g, 0.47 mmol) as a pale yellow solid, yield: 94%, ESI-MS m/z: 1060.3 (M+H); wherein the compound A can be synthesized according to the known method reported in WO2015146132A1. 
     The compound GGFG-Dxd (the structure is as follows) was also synthesized according to the known method reported in WO2015146132A1, ESI-MS m/z: 1034.5 (M+H),  1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.61 (t, J=6.4 Hz, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.28 (t, J=5.1 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 8.05 (t, J=5.7 Hz, 1H), 7.99 (t, J=5.9 Hz, 1H), 7.77 (d, J=11.0 Hz, 1H), 7.31 (s, 1H), 7.25-7.16 (m, 5H), 6.98 (s, 2H), 6.51 (s, 1H), 5.59 (dt, J=7.4, 4.1 Hz, 1H), 5.41 (s, 2H), 5.20 (s, 2H), 4.64 (d, J=6.1 Hz, 2H), 4.53-4.40 (m, 1H), 4.02 (s, 2H), 3.74-3.37 (m, 8H), 3.18-3.00 (m, 2H), 3.04-2.97 (m, 1H), 2.77 (dd, J=13.5, 9.4 Hz, 1H), 2.38 (s, 3H), 2.19 (dd, J=14.9, 8.5 Hz, 2H), 2.11-2.05 (m, 2H), 1.86 (dd, J=14.0, 6.7 Hz, 2H), 1.45 (s, 4H), 1.20-1.14 (m, 2H), 0.87 (t, J=7.1 Hz, 3H). 
     
       
         
         
             
             
         
       
     
     Embodiment 2: Synthesis of LE02-LE06 and LE08 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Referring to Embodiment 1, compounds were obtained by condensation reaction (LE02, LE03 and LE06 need to be acidified after the condensation reaction) between appropriate maleamide fragments with compound A. The structures of the specific maleamide fragments used are shown in Table 2. Compound LE02: pale yellow solid, ESI-MS m/z: 1114.2 (M+H); compound LE03: pale yellow solid, ESI-MS m/z: 1007.2 (M+H); compound LE04: slightly yellow solid, ESI-MS m/z: 1344.5 (M+H); compound LEOS: yellow solid, ESI-MS m/z: 1112.3 (M+H); compound LE06: yellow solid, ESI-MS m/z: 1162.5 (M+H); compound LE08: pale yellow oil, ESI-MS m/z: 1719.1 (M+H). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 The structures of the maleamide fragment used in the synthesis of LE02- 
               
               
                 LE06 and LE08 
               
            
           
           
               
               
            
               
                   
                 Structure of maleamide 
               
               
                 Product 
                 fragment 
               
               
                   
               
               
                 LE02 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE03 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE04 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE05 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE06 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE08 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Embodiment 3: Synthesis of LE07 
     
       
         
         
             
             
         
       
     
     Commercially available LE07-S (1 mmol, 0.34 g) and compound B (0.5 mmol, 0.38 g) were dissolved in 10 mL of DMF; HATU (0.5 mmol, 0.19 g), 0.5 mL of triethylamine were added, and the mixture was stirred at room temperature for 3 h, 0.5 mL of trifluoroacetic acid was added, then the mixture was stirred at room temperature for 10 min, the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform−chloroform:methanol=9:1 (V/V)] to obtain trifluoroacetic acid salt of the title compound (0.33 g, 0.3 mmol) as pale yellow solid, yield: 60%, ESI-MS m/z: 1105.3 (M+H). Compound B can be synthesized according to the known method reported in WO2015146132A1. 
     Embodiment 4: Synthesis of LE09-LE11 
     
       
         
         
             
             
         
       
     
     Referring to the method of Embodiment 3, compounds were obtained by condensation reaction between compound B and appropriate carboxylic acid fragments (commercially available) with a condensing agent. The structures of the specific carboxylic acid fragments used are shown in Table 3. Compound LE09: pale light yellow oil, ESI-MS m/z: 1705.9 (M+H). Compound LE10: ESI-MS: m/z: 1115.9 (M+H),  1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.66 (t, J=6.7 Hz, 1H), 8.53 (d, J=9.0 Hz, 1H), 8.47 (t, J=5.2 Hz, 1H), 8.37 (t, J=5.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 2H), 7.81 (s, 1H), 7.78 (d, J=11.1 Hz, 1H), 7.31 (s, 1H), 7.20 (dd, J=21.9, 7.3 Hz, 5H), 7.00 (d, J=5.3 Hz, 2H), 6.54 (s, 1H), 5.60 (dd, J=13.7, 6.8 Hz, 1H), 5.42 (s, 2H), 5.20 (s, 2H), 5.10 (s, 2H), 4.64 (d, J=6.3 Hz, 2H), 4.55-4.45 (m, 1H), 4.26 (d, J=5.3 Hz, 2H), 4.02 (s, 2H), 3.74 (ddd, J=31.4, 16.7, 5.6 Hz, 6H), 3.17 (dd, J=14.3, 8.5 Hz, 2H), 3.02 (dd, J=14.1, 4.3 Hz, 1H), 2.74 (dd, J=13.4, 10.0 Hz, 1H), 2.38 (s, 3H), 2.23-2.15 (m, 2H), 2.05 (t, J=7.4 Hz, 2H), 1.90-1.80 (m, 2H), 1.46 (dd, J=14.7, 7.3 Hz, 4H), 1.19-1.14 (m, 2H), 0.87 (t, J=7.2 Hz, 3H). Compound LE11: pale yellow solid, ESI-MS m/z: 1141.5 (M+H). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Structures of the carboxylic acid fragments used in the synthesis of LE09- 
               
               
                 LE11 
               
            
           
           
               
               
            
               
                 Product 
                 Structure of carboxylic acid fragment 
               
               
                   
               
               
                 LE09 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Embodiment 5: Synthesis of LE23-LE24 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Commercially available compound LE23-S or LE24-S (2 equivalents) and compound C (1 equivalent) were dissolved in an appropriate amount of DMF, the mixture was stirred at room temperature for 3 h, and the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform-chloroform:methanol=10:1 (V/V)] to obtain the title compound as a pale yellow solid. Wherein, compound C can be synthesized according to the known method reported in WO2015146132A1. Compound LE23: yellow solid, ESI-MS m/z: 1090.2 (M+H); compound LE24: yellow solid, ESI-MS m/z: 1122.1 (M+H). 
     Embodiment 6 Synthesis of LE12 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Synthesis of Intermediate 2 
     (S)-2-azidopropanoic acid (10 g, 86.9 mmol) and 4-aminobenzyl alcohol (21.40 g, 173.8 mmol) were dissolved in 300 mL of a mixed solvent of dichloromethane and methanol (volume ratio: 2:1), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (21.49 g, 86.9 mmol) was added, the reaction was reacted at room temperature for 5 hours, the solvent was evaporated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography [dichloromethane:ethyl acetate=1:1 (v/v)] to obtain Intermediate 2 (16.3 g, yield: 85%), ESI-MS m/z: 221 (M+H). 
     Synthesis of Intermediate 3 
     Intermediate 2 (15 g, 68.2 mmol) and bis(p-nitrophenyl) carbonate (22.82 g, 75.02 mmol) were mixed and dissolved in 200 mL of anhydrous N,N-dimethylformamide, and 25 mL of triethylamine was added, the mixture was reacted at room temperature for 2 hours. After the completion of the reaction of the raw materials was monitored by liquid chromatography-mass spectroscopy, methylamine hydrochloride (6.91 g, 102.3 mmol) was added, and the reaction was continued for 1 hour. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure, and then 200 mL of water and 200 mL of ethyl acetate were added. After the phases were separated, the organic phase was collected, dried and concentrated. The obtained crude product was purified by silica gel column chromatography [dichloromethane:ethyl acetate=10:1 (v/v)] to obtain Intermediate 3 (18.9 g, yield: 100%), ESI-MS m/z: 278 (M+H). 
     Synthesis of Intermediate 5 
     Intermediate 3 (10 g, 36.1 mmol) and paraformaldehyde (1.63 g, 54.2 mmol) were dissolved in 150 mL of anhydrous dichloromethane, trimethylchlorosilane (6.28 g, 57.76 mmol) was slowly added, and the mixture was reacted at room temperature for 2 hours to obtain the solution of crude product of Intermediate 4. After the reaction mixture was sampled, quenched by adding methanol, and the reaction was monitored by LC/MS. After the reaction was completed, the reaction solution was filtered and then tert-butyl glycolate (9.54 g, 72.2 mmol) and triethylamine (10 mL, 72.2 mmol) were added to the filtrate, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [petroleum ether:ethyl acetate=3:1 (v/v)] to obtain Intermediate 5 (11.2 g, yield: 74%), ESI-MS m/z: 422 (M+H). 
     Synthesis of Intermediate 6 
     Intermediate 5 (10 g, 23.8 mmol) was dissolved in 80 mL of anhydrous tetrahydrofuran, 80 mL of water was added, then tris(2-carboxyethyl)phosphine hydrochloride (13.6 g, 47.6 mmol) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure, and then the residue was extracted with ethyl acetate. After the obtained organic phase was dried, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain Intermediate 6 (8.1 g, yield: 86%), ESI-MS m/z: 396 (M+H). 
     Synthesis of Intermediate 8 
     Intermediate 6 (5 g, 12.7 mmol) was dissolved in 60 mL of a mixed solvent of dichloromethane and methanol (v/v=2:1), 3 mL of trifluoroacetic acid was slowly added, and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, equal volumes of water and ethyl acetate were added, the organic phase was dried and then concentrated, and the obtained crude product was directly used in the next step. 
     The crude product obtained in the above step was dissolved in 50 mL of anhydrous N,N-dimethylformamide, Fmoc-valine hydroxysuccinimide ester (8.3 g, 19.1 mmol), triethylamine (5 mL) were added, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain Intermediate 8 (5.4 g, yield: 64%), ESI-MS m/z: 661 (M+H). 
     Synthesis of Intermediate 9 
     Intermediate 8 (1 g, 1.5 mmol) and Exatecan methanesulfonate (0.568 g, 1 mmol) were mixed in 30 mL of anhydrous N,N-dimethylformamide, and 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.0 mmol), 2 mL of triethylamine were added, the mixture was reacted at room temperature for 2 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform:methanol=10:1 (v/v)] to obtain Intermediate 9 (0.94 g, yield 87%), ESI-MS m/z: 1078 (M+H). 
     Synthesis of Compound LE12 
     Intermediate 9 (1 g, 0.929 mmol) was dissolved in 20 mL of anhydrous DMF, 0.5 mL of 1,8-diazabicycloundec-7-ene was added, and the mixture was reacted at room temperature for 1 hour. After the reaction of the raw materials was completed, 6-(maleimido)hexanoic acid succinimidyl ester (428.5 mg, 1.39 mmol) was directly added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform:methanol=8:1 (v/v)] to obtain the title compound (0.7 g, yield: 73%), ESI-MS m/z: 1035 (M+H). 
     Embodiment 7 Synthesis of LE13-LE20 
     
       
         
         
             
             
         
       
     
     Intermediate VI could be prepared by using Fmoc-L-valine-L-alanine as the starting raw material, referring to steps 6a and 6b in the synthesis method of Intermediate 3 in Embodiment 6, wherein the methylamine hydrochloride in step 6b was replaced by corresponding commercially available amino compound. The subsequent steps were started from Intermediate VI, according to the same method as steps 6c, 6d, 6f and 6h in Embodiment 6 to obtain Intermediate IX similar to Intermediate 9, and then according to the same steps as steps 6i and 6j in Embodiment 6 to treat, remove the amino protective group, and then the residue was condensed with commercially available different maleimides to obtain the final product. The amino compounds and maleimide structures used are shown in Table 4. Compound LE13: pale yellow solid, ESI-MS m/z: 1106.5 (M+H); compound LE14: pale yellow solid, ESI-MS m/z: 1141.4 (M+H); compound LE15: off-white solid, ESI-MS m/z: 1121.2 (M+H); compound LE16: pale yellow solid, ESI-MS m/z: 1167.1 (M+H); compound LE17: yellow solid, ESI-MS m/z: 1132.3 (M+H); compound LE18: pale yellow solid, ESI-MS m/z: 1305.4 (M+H); compound LE19: pale yellow solid, ESI-MS m/z: 1307.4 (M+H); compound LE20: pale yellow solid, ESI-MS m/z: 1337.6 (M+H). 
     
       
         
           
               
             
               
                 TABE 4 
               
             
            
               
                   
               
               
                 Intermediates used in the synthesis of LE13-LE20 
               
            
           
           
               
               
               
               
            
               
                 Product 
                 R1 
                 Amino compound 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Dimethyl ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Dimethyl ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 LE20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Methylsulfone ethylamine hydrochloride 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                 
               
            
           
         
       
     
     Embodiment 8 Synthesis of LE21-LE22 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Synthesis of Compound DXD-1 
     Commercially available Exatecan methanesulfonate (0.568 g, 1 mmol) and 2-(tert-butyldimethylsiloxy)acetic acid (CAS: 105459-05-0, 0.38 g, 2 mmol) were dissolved in 20 mL of anhydrous dichloromethane, condensing agent HATU (0.76 g, 2 mmol) and 1 mL of pyridine were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure, and the obtained crude product was purified by column chromatography [dichloromethane:methanol=50:1 (v/v)] to obtain the title compound DXD-1 (0.55 g, yield: 90%), ESI-MS m/z: 608.1 (M+H).  1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J=10.5 Hz, 1H), 7.64 (s, 1H), 7.05 (d, J=9.2 Hz, 1H), 5.80-5.62 (m, 2H), 5.41-5.14 (m, 4H), 4.29-4.15 (m, 2H), 4.08-4.03 (m, 1H), 3.27-3.07 (m, 2H), 2.45 (s, 3H), 2.38-2.28 (m, 2H), 1.96-1.81 (m, 2H), 1.04 (t, J=7.4 Hz, 3H), 0.80 (s, 9H), 0.11 (s, 3H), 0.03 (s, 3H). 
     Preparation of Intermediate V 
     Intermediate V could be prepared by referring to the preparation method of compound 4 in Embodiment 6, wherein the methylamine hydrochloride in step 6b was replaced with the corresponding commercially available amino compound. 
     Synthesis of LE21-LE22 
     Intermediate V was reacted with DXD-1, and then the residue was treated with 10% trifluoroacetic acid/dichloromethane solution to obtain Intermediate X, and then Intermediate X was reacted with reference to the subsequent steps 6e, 6g, 6i and 6j of compound 5 in Embodiment 6: Intermediate X was reduced to obtain an amino compound, the obtained amino compound was condensed with Fmoc-valine hydroxysuccinimide ester, and then the Fmoc protecting group of the amino group in the obtained product was removed, and the obtained amino product was reacted with 6-(maleimido)hexanoic acid succinimidyl ester to obtain the final product. Compound LE21: yellow solid, ESI-MS m/z: 1141.2 (M+H); compound LE22: yellow solid, ESI-MS m/z: 1106.6 (M+H). 
     
       
         
         
             
             
         
       
     
     Embodiment 9: Synthesis of Compound LE13 
     Compound LE13 could be prepared according to the following synthetic route: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The specific preparation steps were as follows: 
     Synthesis of Intermediate 14 
     Commercially available Intermediate 12 (267 mg, 0.8 mmol) and paraformaldehyde (50 mg, 1.6 mmol) were dissolved in 20 mL of anhydrous dichloromethane, and trimethylchlorosilane (0.3 mL, 3.4 mmol) was slowly added, the mixture was reacted at room temperature for 2 hours after the addition was completed. Then the reaction was sampled and quenched by adding methanol to monitor the reaction by liquid chromatography mass spectrometry. After the reaction was completed, the reaction solution was filtered, and then tert-butyl glycolate (211 mg, 1.6 mmol) and 0.5 mL of pempidine were added to the filtrate, and the mixture was reacted at room temperature for about 2 hours. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography [dichloromethane:methanol=20:1 (v/v)] to obtain Intermediate 14 (260 mg, yield: 68%), ESI-MS m/z: 479 (M+H). 
     Synthesis of Intermediate 15 
     Intermediate 14 (238 mg, 0.50 mmol) was dissolved in 6 mL of a mixed solvent of dichloromethane and methanol (v/v=2:1), 0.3 mL of trifluoroacetic acid was slowly added, and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, equal volumes of water and ethyl acetate were added, the organic phase was dried and concentrated, and the obtained crude product was directly used in the next step. 
     Synthesis of Intermediate 16 
     The crude product obtained in the above step and Exatecan methanesulfonate (170 mg, 0.30 mmol) were mixed in 5 mL of anhydrous N,N-dimethylformamide, and 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (341 mg, 0.90 mmol), 0.60 mL of triethylamine were added, the mixture was reacted at room temperature for 2 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform:methanol=10:1 (v/v)] to obtain Intermediate 16 (210 mg, 83%), ESI-MS m/z: 840 (M+H). 
     Synthesis of Intermediate 17 
     Intermediate 16 (100 mg, 0.12 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, 3 mL of water was added, and then 0.3 mL of 1 mol/L triethylphosphine aqueous solution was added, and the mixture was reacted at room temperature for 4 hours. The reaction was monitored until the reaction was completed, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran, sodium bicarbonate was added to the remaining aqueous solution to adjust the pH to neutral, and then dichloromethane was added for extraction. The obtained organic phase was dried and the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain Intermediate 17 (69 mg, yield: 71%), ESI-MS m/z: 814 (M+H). 
     Synthesis of LE13 
     Intermediate 17 (120 mg, 0.15 mmol) obtained in the previous step and the commercially available raw material MC-V (102 mg, 0.33 mmol) were mixed in 40 mL of dichloromethane, and the condensing agent 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (82 mg, 0.33 mmol) was added and the mixture was reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain compound LE13 (116 mg, yield: 70%), ESI-MS m/z: 1106.5 (M+H). 
     Embodiment 10: Synthesis of Compound LE14 
     Compound LE14 could be prepared according to the following synthetic route: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The specific preparation steps were as follows: 
     Synthesis of Intermediate 19 
     Commercially available Intermediate 18 (300 mg, 0.8 mmol) and paraformaldehyde (50 mg, 1.6 mmol) were dissolved in 20 mL of anhydrous dichloromethane, and trimethylchlorosilane (0.3 mL, 3.4 mmol) was slowly added, the mixture was reacted at room temperature for 2 hours. Then the reaction was sampled and quenched by adding methanol to monitor the reaction by liquid chromatography mass spectrometry. After the reaction was completed, the reaction solution was filtered, and then tert-butyl glycolate (211 mg, 1.6 mmol) and triethylamine (0.22 m, 1.6 mmol) were added to the filtrate, and the mixture was reacted at room temperature for about 2 hours. After the reaction was completed, most of the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol=20:1 (v/v)] to obtain Intermediate 19 (349 mg, yield 85%), ESI-MS m/z: 514 (M+H),  1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.56 (d, J=7.5 Hz, 2H), 7.35 (s, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 4.25 (q, J=7.1 Hz, 1H), 3.99 (d, J=42.5 Hz, 2H), 3.85 (t, J=6.2 Hz, 2H), 3.40 (dd, J=18.5, 7.6 Hz, 2H), 2.89 (d, J=48.6 Hz, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.46 (s, 9H). 
     Synthesis of Intermediate 20 
     Intermediate 19 (257 mg, 0.50 mmol) was dissolved in 6 mL of a mixed solvent of dichloromethane and methanol (v/v=2:1), 0.3 mL of trifluoroacetic acid was slowly added, and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, equal volumes of water and ethyl acetate were added, the organic phase was dried and concentrated, and the obtained crude product was directly used in the next step. 
     The obtained crude product and Exatecan methanesulfonate (170 mg, 0.30 mmol) were mixed in 5 mL of anhydrous N,N-dimethylformamide, and 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (341 mg, 0.90 mmol), 0.60 mL of triethylamine were added, the mixture was reacted at room temperature for 2 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by silica gel column chromatography [chloroform:methanol=20:1 (v/v)] to obtain Intermediate 20 (212 mg, yield: 81%), ESI-MS m/z: 875 (M+H).  1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J=34.7 Hz, 1H), 7.63-7.35 (m, 5H), 7.21-7.10 (m, 1H), 5.71-5.48 (m, 2H), 5.24-4.95 (m, 3H), 4.95-4.72 (m, 4H), 4.45 (s, 1H), 4.33-3.97 (m, 3H), 3.75 (s, 2H), 3.39-2.99 (m, 4H), 2.76 (d, J=15.3 Hz, 3H), 2.43-2.15 (m, 5H), 2.04 (s, 1H), 1.94-1.75 (m, 2H), 1.62 (d, J=6.6 Hz, 3H), 1.11-0.89 (m, 3H). 
     Synthesis of Intermediate 21 
     Intermediate 20 (77 mg, 0.09 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran, 3 mL of water was added, and then 0.3 mL of 1 mol/L triethylphosphine aqueous solution was added, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, tetrahydrofuran was removed by distillation under reduced pressure, sodium bicarbonate was added to the remaining aqueous solution to adjust the pH to neutral, and then dichloromethane was added for extraction. The obtained organic phase was dried and the solvent was evaporated under reduced pressure, the obtained crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain Intermediate 21 (53 mg, yield: 69%), ESI-MS m/z: 849 (M+H).  1 H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 7.79 (d, J=10.8 Hz, 1H), 7.67-7.55 (m, 2H), 7.47-7.21 (m, 3H), 6.51 (s, 1H), 5.60 (s, 1H), 5.52-5.32 (m, 2H), 5.30-5.11 (m, 2H), 5.11-4.94 (m, 2H), 4.94-4.74 (m, 2H), 4.02 (s, 2H), 3.81-3.66 (m, 2H), 3.60-3.35 (m, 4H), 3.24-3.08 (m, 2H), 2.94 (d, J=30.8 Hz, 3H), 2.39 (s, 3H), 2.28-2.04 (m, 2H), 2.00-1.73 (m, 2H), 1.22 (d, J=6.6 Hz, 3H), 0.96-0.70 (m, 3H). 
     Synthesis of Compound LE14 
     Intermediate 21 (134 mg, 0.16 mmol) and commercially available raw material MC-V (102 mg, 0.33 mmol) were mixed in 40 mL of dichloromethane, and the condensing agent 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (82 mg, 0.33 mmol) was added and the mixture was reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography [dichloromethane:methanol=10:1 (v/v)] to obtain compound LE14 (137 mg, yield: 75%), ESI-MS m/z: 1141.4 (M+H).  1 H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.52 (s, 1H), 8.27-8.09 (m, 1H), 7.88-7.70 (m, 2H), 7.63-7.51 (m, 2H), 7.28 (s, 3H), 6.99 (s, 2H), 6.51 (s, 1H), 5.59 (s, 1H), 5.50-5.32 (m, 2H), 5.17 (s, 2H), 4.98 (s, 2H), 4.85 (d, J=17.3 Hz, 2H), 4.43-4.33 (m, 1H), 4.21-4.12 (m, 1H), 4.03 (s, 2H), 3.74-3.64 (m, 2H), 3.20-3.03 (m, 3H), 3.02-2.84 (m, 4H), 2.36 (s, 3H), 2.23-2.09 (m, 4H), 2.01-1.90 (m, 1H), 1.90-1.78 (m, 2H), 1.55-1.39 (m, 4H), 1.30 (d, J=6.7 Hz, 3H), 1.23-1.11 (m, 2H), 0.93-0.77 (m, 9H). 
     Embodiment 11: Synthesis of Compound LS13 
     Referring to the synthesis method of LE14 in Embodiment 7, after SN-38 (7-ethyl-10-hydroxycamptothecin) was reacted with Intermediate VII (R 1  is methylsulfone ethyl), the compound LS13 was obtained by deprotection, condensation and other steps:  1 H NMR (400 MHz, DMSO) δ 9.92 (d, J=22.4 Hz, 1H), 8.14 (s, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70-7.50 (m, 3H), 7.47 (d, J=7.2 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 6.98 (s, 2H), 6.51 (s, 1H), 5.61 (s, 2H), 5.48-5.35 (m, 2H), 5.27 (s, 2H), 5.10 (d, J=20.6 Hz, 2H), 4.36 (s, 1H), 4.21-4.07 (m, 1H), 3.84 (s, 2H), 3.48 (s, 2H), 3.21-2.92 (m, 6H), 2.25-2.04 (m, 2H), 2.04-1.78 (m, 3H), 1.55-1.36 (m, 4H), 1.36-1.10 (m, 9H), 0.95-0.71 (m, 10H). 
     
       
         
         
             
             
         
       
     
     Embodiment 12: General Method for Connecting Linker-Drug Conjugates to Antibodies 
     The anti-B7-H3 antibody P2E5, anti-Claudin18.2 antibody IMAB362, and anti-HER2 antibody Trastuzumab (concentration was 15 mg/mL) were replaced into 50 mM PB/1.0 mM EDTA buffer (pH 7.0) by a G25 desalting column, respectively. 12 equivalents of TECP was added and the mixture was stirred at 37° C. for 2 hours to fully open the disulfide bonds between the antibody chains. Then phosphoric acid was used to adjust the pH of the reduced antibody solution to 6.0, and the temperature of the water bath was lowered to 25° C. for coupling reaction. The linker-drug conjugate prepared in Embodiments 1-11 and GGFG-Dxd were respectively dissolved in DMSO, and 12 equivalents of the linker-drug conjugate was drawn and added dropwise into the reduced antibody solution, and DMSO was added until final concentration of the solution was 10% (v/v), the mixture was stirred and reacted at 25° C. for 0.5 hours. After the reaction was completed, the sample was filtered with a 0.22 μm membrane. Uncoupled small molecules were purified and removed by a tangential flow ultrafiltration system. The buffer was 50 mM PB/1.0 mM EDTA solution (pH 6.0). After purification, sucrose (final concentration was 6%) was added, and the mixture was stored in a refrigerator at −20° C. The UV method was used to measure the absorbance values at 280 nm and 370 nm respectively, and the DAR value was calculated. The results are shown in Table 5 below. The amino acid sequence of the light chain in the anti-HER2 antibody Trastuzumab is shown in SEQ ID No. 5 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-HER2 antibody Trastuzumab is shown in SEQ ID No. 6 in the sequence listing. The amino acid sequence of the light chain in the anti-B7-H3 antibody P2E5 is shown in SEQ ID No. 7 in the sequence listing, and the amino acid sequence of the heavy chain in the anti-B7-H3 antibody P2E5 is shown in SEQ ID No. 8 in the sequence listing. The amino acid sequence of the light chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 1 in the sequence table, and the amino acid sequence of the heavy chain in the anti-Claudin 18.2 antibody IMAB362 is shown in SEQ ID No. 2 in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 DAR values of different antibody drug conjugates 
               
               
                 (ADC) measured under UV method 
               
            
           
           
               
               
               
               
            
               
                 No. ADC 
                 Antibody 
                 Linker-drug conjugate 
                 DAR value 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 ADC-8201 
                 Trastuzumab 
                 GGFG-Dxd 
                 7.6 
               
               
                 ADC001 
                 Trastuzumab 
                 LE01 
                 7.6 
               
               
                 ADC002 
                 Trastuzumab 
                 LE02 
                 7.8 
               
               
                 ADC003 
                 Trastuzumab 
                 LE03 
                 7.4 
               
               
                 ADC004 
                 Trastuzumab 
                 LE04 
                 7.5 
               
               
                 ADC005 
                 Trastuzumab 
                 LE06 
                 7.5 
               
               
                 ADC006 
                 Trastuzumab 
                 LE10 
                 7.3 
               
               
                 ADC007 
                 Trastuzumab 
                 LE13 
                 7.7 
               
               
                 ADC008 
                 Trastuzumab 
                 LE15 
                 7.7 
               
               
                 ADC009 
                 Trastuzumab 
                 LE18 
                 7.8 
               
               
                 ADC010 
                 Trastuzumab 
                 LE19 
                 7.5 
               
               
                 ADC011 
                 Trastuzumab 
                 LE20 
                 7.5 
               
               
                 ADC029 
                 Trastuzumab 
                 LE14 
                 8.0 
               
               
                 ADC030 
                 Trastuzumab 
                 LS13 
                 8.0 
               
               
                 ADC033 
                 Trastuzumab 
                 LE12 
                 7.8 
               
               
                 ADC012 
                 P2E5 
                 LE01 
                 7.6 
               
               
                 ADC013 
                 P2E5 
                 LE02 
                 7.4 
               
               
                 ADC014 
                 P2E5 
                 LE03 
                 7.6 
               
               
                 ADC015 
                 P2E5 
                 LE04 
                 7.5 
               
               
                 ADC016 
                 P2E5 
                 LE06 
                 7.4 
               
               
                 ADC017 
                 P2E5 
                 LE10 
                 7.5 
               
               
                 ADC018 
                 P2E5 
                 LE13 
                 7.6 
               
               
                 ADC019 
                 P2E5 
                 LE15 
                 7.6 
               
               
                 ADC020 
                 P2E5 
                 LE01 
                 7.5 
               
               
                 ADC031 
                 P2E5 
                 LE14 
                 7.8 
               
               
                 ADC034 
                 P2E5 
                 LE12 
                 7.7 
               
               
                 ADC021 
                 IMAB362 
                 LE02 
                 7.5 
               
               
                 ADC022 
                 IMAB362 
                 LE03 
                 7.5 
               
               
                 ADC023 
                 IMAB362 
                 LE04 
                 7.7 
               
               
                 ADC024 
                 IMAB362 
                 LE06 
                 7.4 
               
               
                 ADC025 
                 IMAB362 
                 LE10 
                 7.6 
               
               
                 ADC026 
                 IMAB362 
                 LE13 
                 7.8 
               
               
                 ADC027 
                 IMAB362 
                 LE15 
                 7.5 
               
               
                 ADC028 
                 IMAB362 
                 LE18 
                 7.6 
               
               
                 ADC032 
                 IMAB362 
                 LE14 
                 7.6 
               
               
                 ADC035 
                 IMAB362 
                 LE12 
                 7.5 
               
               
                   
               
            
           
         
       
     
     Effect Embodiment 1: In Vitro Cell Activity Test 
     The HEK293 cells stably transfected with high expression of Claudin 18.2, SK-BR-3 and NCI-N87 cells with high expression of HER2 were selected as the cell lines for in vitro activity detection in this experiment. NCI-N87 cells also highly expressed B7-H3. The dose effect of different antibody drug conjugates on cell killing were observed. The seed plate density of each cell was preliminarily selected: 2×10 3  cells/well, and the cytotoxic activity was tested after 16 to 24 hours; secondly, the final concentration of antibody drug conjugate prepared in Embodiment 12 after loading was tested, and the initial concentration was set at 5000 nM. Series of 10 concentrations was designed in 5000-0.006 nM (4-10 times diluted), the killing (or inhibition) changes in 96 hours was observed, chemiluminescence staining was performed by CellTiter-Glo® Luminescent Cell Viability Assay, IC 50  was calculated after reading the fluorescence data. From the activity test results (see Table 6), all ADCs show certain anti-tumor activity, and the activity of some ADCs are better than ADC-8201. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 In vitro cytotoxic activity of different ADCs 
               
            
           
           
               
               
               
            
               
                   
                 IC 50 (nM) 
                   
               
            
           
           
               
               
               
               
            
               
                 No. ADC 
                 SK-BR-3 cell 
                 NCI-N87 cell 
                 HEK293 cell 
               
               
                   
               
               
                 ADC-8201 
                 0.729 
                 0.586 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC001 
                 0.535 
                 0.651 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC002 
                 0.683 
                 0.468 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC003 
                 0.411 
                 0.510 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC004 
                 0.951 
                 1.256 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC005 
                 5.609 
                 3.595 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC006 
                 0.362 
                 0.419 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC007 
                 0.185 
                 0.278 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC008 
                 0.103 
                 0.169 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC009 
                 0.297 
                 0.190 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC010 
                 0.334 
                 0.624 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC011 
                 0.621 
                 0.323 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC029 
                 0.480 
                 0.641 
                 Not tested 
               
            
           
           
               
               
               
               
               
            
               
                 ADC030 
                 15 μM * 
                 11 
                 μM * 
                 Not tested 
               
            
           
           
               
               
               
               
            
               
                 ADC033 
                 0.615 
                 0.701 
                 Not tested 
               
               
                 ADC012 
                 Not tested 
                 1.690 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC013 
                 Not tested 
                 3.158 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC014 
                 Not tested 
                 2.160 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC015 
                 Not tested 
                 1.578 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC016 
                 Not tested 
                 1.268 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC017 
                 Not tested 
                 1.463 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
            
           
           
               
               
               
               
               
            
               
                 ADC018 
                 Not tested 
                 10.361 
                 nM 
                 greater than 
               
               
                   
                   
                   
                   
                 5 μM 
               
            
           
           
               
               
               
               
            
               
                 ADC019 
                 Not tested 
                 2.891 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC020 
                 Not tested 
                 0.863 
                 greater than 
               
               
                   
                   
                   
                 5 μM 
               
               
                 ADC031 
                 Not tested 
                 0.732 
                 Not tested 
               
               
                 ADC034 
                 Not tested 
                 0.624 
                 Not tested 
               
               
                 ADC021 
                 Not tested 
                 greater than 
                 0.278 
               
               
                   
                   
                 5 μM 
               
               
                 ADC022 
                 Not tested 
                 greater than 
                 0.676 
               
               
                   
                   
                 5 μM 
               
               
                 ADC023 
                 Not tested 
                 greater than 
                 0.335 
               
               
                   
                   
                 5 μM 
               
               
                 ADC024 
                 Not tested 
                 greater than 
                 0.125 
               
               
                   
                   
                 5 μM 
               
               
                 ADC025 
                 Not tested 
                 greater than 
                 0.924 
               
               
                   
                   
                 5 μM 
               
               
                 ADC026 
                 Not tested 
                 greater than 
                 0.115 
               
               
                   
                   
                 5 μM 
               
               
                 ADC027 
                 Not tested 
                 greater than 
                 0.364 
               
               
                   
                   
                 5 μM 
               
               
                 ADC028 
                 Not tested 
                 greater than 
                 0.824 
               
               
                   
                   
                 5 μM 
               
               
                 ADC032 
                 Not tested 
                 greater than 
                 0.391 
               
               
                   
                   
                 5 μM 
               
               
                 ADC035 
                 Not tested 
                 Not tested 
                 0.352 
               
               
                   
               
               
                 * This data was obtained according to the same experimental operation as that of this effect embodiment based on the initial concentration of 30 μM. 
               
            
           
         
       
     
     Effect Embodiment 2: In Vitro Plasma Stability Test 
     This embodiment evaluates the stability of the antibody drug conjugate of Embodiment 12 in human plasma. Specifically, in this embodiment, part of the antibody drug conjugates of Embodiment 12 were added to human plasma and placed in a 37° C. water bath for 1, 3, 7, 14, 21, 28 days, internal standard (Exatecan was used as an internal standard substance) was added, and the mixture was extracted and then the release amount of free drug was detected by high performance liquid chromatography. The results are shown in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Evaluation of the stability of different ADCs in human plasma 
               
            
           
           
               
               
            
               
                   
                 Ratio of free drug 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Sample name 
                 Day 1 
                 Day 3 
                 Day 7 
                 Day 14 
                 Day 21 
                 Day 28 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 ADC-8201 
                 0.4% 
                 0.7% 
                 0.9% 
                 1.3% 
                 1.1% 
                 2.5% 
               
               
                 ADC001 
                 0.3% 
                 0.8% 
                 0.9% 
                 1.2% 
                 1.0% 
                 2.0% 
               
               
                 ADC007 
                 0.1% 
                 0.3% 
                 0.6% 
                 0.7% 
                 1.0% 
                 1.5% 
               
               
                 ADC008 
                 0.2% 
                 0.3% 
                 0.5% 
                 0.8% 
                 0.9% 
                 1.1% 
               
               
                 ADC010 
                 0.5% 
                 0.6% 
                 0.8% 
                 1.0% 
                 1.2% 
                 2.0% 
               
               
                 ADC011 
                 0.4% 
                 0.7% 
                 1.1% 
                 1.3% 
                 1.8% 
                 2.5% 
               
               
                 ADC029 
                 0.2% 
                 0.3% 
                 0.8% 
                 1.1% 
                 1.3% 
                 1.5% 
               
               
                 ADC030 
                 0.2% 
                 0.9% 
                 2.0% 
                 3.5% 
                 4.7% 
                 5.5% 
               
               
                   
               
            
           
         
       
     
     Plasma stability results show that the ADC stability obtained by the new technical solution is not inferior to ADC-8201, and some of them are more stable. At the same time, the above activity test results also prove that the activities of some of the newly obtained ADC are better than ADC-8201. 
     Effect Embodiment 3: Evaluation of Different Linker-Drug Conjugates 
     When the linker-drug conjugate was coupled with different antibodies, the universality of the linker-drug conjugate was reflected in the aggregates, recovery rate and whether the precipitation was occurred, etc. Although Trastuzumab did not produce precipitation during the coupling process with the linker-drug conjugate of ADC-8201 (GGFG-Dxd), among the antibodies listed in the present disclosure, the P2E5 and IMAB362 antibodies produced precipitation during the coupling process with GGFG-Dxd. Therefore, P2E5, IMAB362 and Trastuzumab were selected to evaluate universality of the linker-drug conjugate of the present disclosure in this experiment, the coupling reactions were performed according to the method in Embodiment 12, the samples were prepared according to the highest DAR (i.e., excessive coupling) and the results are shown in Table 8. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 The situations of different linker-drug conjugates when coupled with different antibodies 
               
            
           
           
               
               
               
               
            
               
                   
                 Coupling situation 
                 Coupling situation 
                 Coupling situation 
               
               
                   
                 of P2E5 
                 of IMAB362 
                 of Trastuzumab 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Linker-drug 
                 Whether 
                 Ratio of 
                 Recovery 
                 Whether 
                 Ratio of 
                 Recovery 
                 Whether 
                 Ratio of 
                 Recovery 
               
               
                 conjugate 
                 precipitation 
                 aggregates 
                 rate 
                 precipitation 
                 aggregates 
                 rate 
                 precipitation 
                 aggregates 
                 rate 
               
               
                   
               
               
                 GGFG-Dxd 
                 precipitation 
                  20% 
                 30% 
                 precipitation 
                  35% 
                 32% 
                 No 
                 0.1% 
                 90% 
               
               
                 LE01 
                 No 
                 2.1% 
                 / 
                 No 
                 2.0% 
                 / 
                 No 
                 0.2% 
                 80% 
               
               
                 LE02 
                 No 
                 1.3% 
                 / 
                 No 
                 1.8% 
                 / 
                 No 
                 0.2% 
                 80% 
               
               
                 LE03 
                 No 
                 1.1% 
                 80% 
                 No 
                 1.5% 
                 86% 
                 No 
                 0.2% 
                 87% 
               
               
                 LE04 
                 No 
                 2.5% 
                 76% 
                 No 
                 2.1% 
                 85% 
                 No 
                 0.1% 
                 88% 
               
               
                 LE05 
                 No 
                 1.6% 
                 80% 
                 No 
                 2.3% 
                 82% 
                 No 
                 0.1% 
                 86% 
               
               
                 LE06 
                 No 
                 1.2% 
                 72% 
                 No 
                 1.7% 
                 / 
                 No 
                 0.5% 
                 85% 
               
               
                 LE07 
                 No 
                 1.3% 
                 / 
                 No 
                 1.6% 
                 / 
                 No 
                 0.5% 
                 / 
               
               
                 LE08 
                 No 
                 2.2% 
                 / 
                 No 
                 2.3% 
                 / 
                 No 
                 0.2% 
                 / 
               
               
                 LE09 
                 No 
                 2.6% 
                 90% 
                 No 
                 1.5% 
                 90% 
                 No 
                 0.1% 
                 / 
               
               
                 LE10 
                 No 
                 2.5% 
                 85% 
                 No 
                 1.2% 
                 88% 
                 No 
                 0.1% 
                 90% 
               
               
                 LE11 
                 No 
                 3.1% 
                 79% 
                 No 
                 1.4% 
                 82% 
                 No 
                 0.2% 
                 90% 
               
               
                 LE12 
                 No 
                 1.0% 
                 83% 
                 No 
                 2.9% 
                 / 
                 No 
                 0.3% 
                 86% 
               
               
                 LE13 
                 No 
                 1.5% 
                 / 
                 No 
                 2.3% 
                 / 
                 No 
                 0.1% 
                 85% 
               
               
                 LE14 
                 No 
                 1.3% 
                 / 
                 No 
                 2.5% 
                 / 
                 No 
                 0.3% 
                 91% 
               
               
                 LE15 
                 No 
                 2.1% 
                 / 
                 No 
                 1.6% 
                 / 
                 No 
                 0.2% 
                 90% 
               
               
                 LE16 
                 No 
                 2.0% 
                 / 
                 No 
                 1.5% 
                 / 
                 No 
                 0.5% 
                 80% 
               
               
                 LE17 
                 No 
                 1.5% 
                 / 
                 No 
                 1.6% 
                 / 
                 No 
                 0.1% 
                 82% 
               
               
                 LE18 
                 No 
                 1.6% 
                 / 
                 No 
                 2.1% 
                 / 
                 No 
                 0.1% 
                 95% 
               
               
                 LE19 
                 No 
                 1.2% 
                 / 
                 No 
                 1.4% 
                 / 
                 No 
                 0.2% 
                 90% 
               
               
                 LE20 
                 No 
                 3.0% 
                 / 
                 No 
                 1.2% 
                 / 
                 No 
                 0.2% 
                 80% 
               
               
                 LE21 
                 No 
                 2.2% 
                 / 
                 No 
                 2.3% 
                 / 
                 No 
                 0.2% 
                 90% 
               
               
                 LE22 
                 No 
                 2.1% 
                 / 
                 No 
                 1.5% 
                 / 
                 No 
                 0.5% 
                 90% 
               
               
                 LE23 
                 No 
                 1.9% 
                 / 
                 No 
                 1.6% 
                 / 
                 No 
                 0.1% 
                 88% 
               
               
                 LE24 
                 No 
                 1.2% 
                 / 
                 No 
                 2.0% 
                 / 
                 No 
                 0.1% 
                 92% 
               
               
                   
               
               
                 “/” means the recovery rate is not calculated. 
               
            
           
         
       
     
     In actual research, it was also found that precipitation would be produced when the linker-drug conjugate of ADC-8201 (GGFG-Dxd) was coupled with other antibodies, and the ratio of aggregates was high, which was not universal. However, most of the linker-drug conjugates in this technical solution were coupled with different antibodies, and no precipitation was produced, and the ratio of aggregates was in the normal range, indicating that the linker-drug conjugates in the present disclosure have better physical and chemical properties. 
     Effect Embodiment 4: In Vitro Enzyme Cleavage Experiment of Linker-Drug Conjugates 
     Linker-drug conjugates (LE14 and GGFG-Dxd) and cathepsin B were incubated in three different pH (5.0, 6.0, 7.0) buffers, and samples were taken at different time points into the high performance liquid chromatography-mass spectrometer. The release percentage of the drug was determined by external standard method (with Dxd as the external standard). The experimental results (shown in Table 9) show that GGFG-Dxd has a slower enzyme cleavage speed in the pH range used, while the LE14 of the present disclosure could quickly cleave in the range of pH 5.0 to pH 7.0. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Enzyme cleavage of LE14 and GGFG-Dxd at different pH in vitro 
               
            
           
           
               
               
            
               
                   
                 Release percentage of drug in samples % 
               
            
           
           
               
               
               
            
               
                   
                 GGFG-Dxd 
                 LE14 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Time (h) 
                 pH 5.0 
                 pH 6.0 
                 pH 7.0 
                 pH 5.0 
                 pH 6.0 
                 pH 7.0 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 0 
                 21.62 
                 23.58 
                 22.98 
                 15 
                 14.28 
                 17.59 
               
               
                 1 
                 25 
                 24.8 
                 26.53 
                 96.93 
                 95.98 
                 98.05 
               
               
                 2 
                 25.85 
                 27.02 
                 29.52 
                 98.35 
                 96.8 
                 99.08 
               
               
                 3 
                 27.76 
                 29.29 
                 31.95 
                 99.01 
                 98.45 
                 99.33 
               
               
                 4 
                 29.72 
                 31.37 
                 34.78 
                 99.21 
                 98.81 
                 99.2 
               
               
                 5 
                 31.69 
                 33.05 
                 36.17 
                 99.32 
                 98.9 
                 100 
               
               
                 6 
                 34.17 
                 35.95 
                 38.25 
                 97.39 
                 99 
                 99.39 
               
               
                   
               
            
           
         
       
     
     Effect Embodiment 5: In Vitro Enzyme Cleavage Experiment of ADC030 
     The NCI-N87 cell line was selected as the experimental cell line. After the sample was incubated in the cathepsin B system (100 mM sodium acetate-acetic acid buffer, 4 mM dithiothreitol, pH 5.0) at 37° C. for 4 hours, the obtained sample was diluted to different concentrations by culture medium, 8 concentrations (1.5-10 times diluted) were set in 70 nM-0.003 nM according to SN-38 concentration, the changes in the killing (inhibition) ability for the cell line for 144 hours were observed, and chemiluminescence staining was performed by CellTiter-Glo® Luminescent Cell Viability Assay, IC 50  value was calculated after reading the fluorescence data. 
     The sample of enzyme cleavage obtained by incubating in the cathepsin B system at 37° C. for 4 hours was subjected to an appropriate amount of ethanol to precipitate and remove the protein, and the released small molecule compounds were detected by high performance liquid chromatography, and the equal amount of SN-38 was used as a reference. The release rate at 4 hours was detected, the results showed that the release rate reached 99%. 
     The experimental results (shown in Table 10) show that the cytotoxic activity of ADC030 after enzyme cleavage was almost the same as that of equivalent amount of SN-38, also show that ADC030 almost completely releases SN-38 and functions with the action of cathepsin B. However, the endocytosis of ADC030 into the lysosome might cause unpredictable changes to cause SN-38 to not function effectively. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Changes in the killing activity of ADC030 on NCI-N87 cell 
               
               
                 line before and after enzyme cleavage by cathepsin B system 
               
            
           
           
               
               
               
            
               
                   
                 IC 50  (Based on SN-38 equivalent, nM) 
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Sample 
                 Before enzyme cleavage 
                 After enzyme cleavage 
               
               
                   
                   
               
               
                   
                 ADC030 
                 greater than70 nM 
                 7.011 nM 
               
               
                   
                 SN38 
                 6.471 nM 
                 6.853 nM 
               
               
                   
                   
               
            
           
         
       
     
     Effect Embodiment 6: In Vivo Evaluation 1 
     Female Balb/c nude mice aged 6-8 weeks were injected subcutaneously on the back of the neck with 5×10 6  human pancreatic cancer cells (Capan-1) dissolved in 100 μL of PBS solution. When the average tumor volume was about 160 mm 3 , the nude mice were randomly grouped according to the tumor size. The 36 nude mice were randomly divided into 6 groups with 6 animals in each group, and the group was administered by tail vein injection: 01 was the blank control group, and 02 was the ADC-8201 (5 mg/kg), 03 was ADC-8201 (2 mg/kg), 04 was ADC-029 (5 mg/kg), 05 was ADC-029 (2 mg/kg), 06 was ADC-030 (5 mg/kg), administered once. The body weight and tumor volume of the experimental animals were measured twice a week, and the survival status of the animals was observed during the experiment. The experimental results (shown in Table 11) show that ADC029 has good anti-tumor activity in vivo. At the same time, all experimental mice have no death or weight loss, indicating that ADC029 has good safety. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 In vivo efficacy evaluation experiment results of ADCs 
               
            
           
           
               
               
            
               
                   
                 Observation days 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Group 
                 13 
                 15 
                 19 
                 22 
                 26 
                 29 
                 33 
                 36 
                 40 
                 43 
               
               
                   
               
            
           
           
               
            
               
                 Average tumor volume/mm 3   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 01 
                 165.97 
                 188.05 
                 220.11 
                 288.34 
                 375.37 
                 487.37 
                 652.21 
                 731.11 
                 886.69 
                 1013.90 
               
               
                 02 
                 166.24 
                 191.68 
                 120.85 
                 97.49 
                 84.33 
                 78.49 
                 84.20 
                 84.11 
                 87.65 
                 91.82 
               
               
                 03 
                 165.86 
                 179.77 
                 117.95 
                 112.81 
                 110.70 
                 96.03 
                 95.66 
                 105.63 
                 142.51 
                 189.84 
               
               
                 04 
                 166.11 
                 174.06 
                 103.92 
                 80.47 
                 57.99 
                 46.15 
                 36.92 
                 35.36 
                 49.96 
                 47.78 
               
               
                 05 
                 166.47 
                 193.01 
                 130.30 
                 120.07 
                 118.62 
                 123.08 
                 154.60 
                 178.78 
                 212.77 
                 236.80 
               
               
                 06 
                 165.97 
                 189.25 
                 206.11 
                 268.34 
                 335.26 
                 427.46 
                 552.21 
                 611.66 
                 726.69 
                 832.58 
               
            
           
           
               
            
               
                 Standard deviation 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 01 
                 8.80 
                 11.86 
                 10.55 
                 25.68 
                 42.69 
                 60.51 
                 86.63 
                 100.19 
                 118.87 
                 143.97 
               
               
                 02 
                 10.16 
                 10.13 
                 10.78 
                 11.27 
                 14.13 
                 15.29 
                 19.38 
                 22.54 
                 29.99 
                 37.98 
               
               
                 03 
                 8.46 
                 5.52 
                 9.79 
                 11.62 
                 12.07 
                 14.78 
                 19.00 
                 16.67 
                 30.07 
                 42.31 
               
               
                 04 
                 10.26 
                 10.76 
                 10.85 
                 8.58 
                 11.41 
                 12.49 
                 9.57 
                 9.89 
                 16.65 
                 15.96 
               
               
                 05 
                 9.67 
                 17.59 
                 12.76 
                 13.26 
                 20.41 
                 32.95 
                 39.89 
                 53.93 
                 70.96 
                 80.51 
               
               
                 06 
                 9.10 
                 10.86 
                 11.27 
                 20.54 
                 33.63 
                 40.89 
                 66.52 
                 87.45 
                 90.87 
                 124.27 
               
               
                   
               
            
           
         
       
     
     Effect 7: In Vivo Evaluation 2 
     Female Balb/c nude mice aged 6-8 weeks were injected subcutaneously on the right of back of the neck with 1×10 7  human gastric cancer cells (NCI-N87) dissolved in 100 μL of PBS solution. When the average tumor volume was about 200 mm 3 , the nude mice were randomly grouped according to the tumor size. The 42 nude mice were randomly divided into 7 groups with 6 animals in each group, and the group was administered by tail vein injection: 01 was the blank control group, and 02 was the ADC-8201 (2 mg/kg), 03 was ADC-8201 (1 mg/kg), 04 was ADC-029 (4 mg/kg), 05 was ADC-029 (2 mg/kg), 06 was ADC-029 (1 mg/kg), 07 was ADC-030 (4 mg/kg), administered once. The body weight and tumor volume of the experimental animals were measured twice a week, and the survival status of the animals was observed during the experiment. The experimental results (shown in Table 12) show that ADC029 has good anti-tumor activity in vivo. At the same time, all experimental mice have no death or weight loss, indicating that ADC029 has good safety. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 In vivo efficacy evaluation experiment results of ADCs 
               
            
           
           
               
               
            
               
                   
                 Observation days 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Group 
                 5 
                 7 
                 11 
                 14 
                 18 
                 21 
                 25 
                 28 
                 32 
                 35 
                 39 
               
               
                   
               
            
           
           
               
            
               
                 Average tumor volume/mm 3   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 01 
                 205.31 
                 283.81 
                 395.50 
                 489.36 
                 621.74 
                 721.41 
                 783.85 
                 890.79 
                 994.80 
                 1176.92 
                 1348.83 
               
               
                 02 
                 205.35 
                 260.96 
                 235.65 
                 202.27 
                 250.53 
                 341.51 
                 363.76 
                 412.44 
                 479.74 
                 527.30 
                 655.96 
               
               
                 03 
                 205.54 
                 315.13 
                 332.46 
                 284.41 
                 419.84 
                 489.93 
                 529.24 
                 628.75 
                 725.02 
                 892.29 
                 1065.85 
               
               
                 04 
                 206.12 
                 272.70 
                 183.81 
                 92.97 
                 86.30 
                 103.46 
                 120.85 
                 134.44 
                 190.95 
                 205.07 
                 260.94 
               
               
                 05 
                 206.94 
                 339.51 
                 268.58 
                 192.55 
                 191.16 
                 217.61 
                 250.78 
                 273.13 
                 324.77 
                 368.20 
                 426.12 
               
               
                 06 
                 205.32 
                 296.64 
                 320.03 
                 307.45 
                 386.87 
                 510.03 
                 595.45 
                 699.04 
                 809.63 
                 922.72 
                 1192.74 
               
               
                 07 
                 205.41 
                 292.72 
                 355.89 
                 449.40 
                 521.77 
                 701.56 
                 752.56 
                 830.29 
                 924.29 
                 989.50 
                 1248.83 
               
            
           
           
               
            
               
                 Standard deviation 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 01 
                 11.93 
                 26.98 
                 38.06 
                 34.44 
                 32.84 
                 19.24 
                 21.21 
                 35.51 
                 47.44 
                 75.40 
                 72.37 
               
               
                 02 
                 11.17 
                 23.58 
                 35.14 
                 36.43 
                 47.43 
                 59.92 
                 56.95 
                 73.14 
                 88.12 
                 90.84 
                 135.74 
               
               
                 03 
                 11.39 
                 29.11 
                 42.69 
                 50.34 
                 85.78 
                 88.24 
                 100.84 
                 111.58 
                 131.43 
                 180.36 
                 196.79 
               
               
                 04 
                 12.53 
                 33.17 
                 38.18 
                 15.98 
                 19.11 
                 28.83 
                 40.77 
                 46.78 
                 59.68 
                 59.36 
                 65.89 
               
               
                 05 
                 12.72 
                 23.80 
                 30.81 
                 36.69 
                 47.20 
                 72.84 
                 83.71 
                 87.46 
                 101.84 
                 113.68 
                 142.41 
               
               
                 06 
                 10.90 
                 32.35 
                 33.83 
                 34.59 
                 44.27 
                 43.55 
                 68.98 
                 57.29 
                 87.10 
                 89.34 
                 136.02 
               
               
                 07 
                 12.69 
                 30.12 
                 39.85 
                 39.29 
                 54.12 
                 62.53 
                 78.29 
                 94.24 
                 100.22 
                 111.47 
                 137.98 
               
               
                   
               
            
           
         
       
     
     Effect Embodiment 8: Safety Evaluation 
     The male and female ICR mice were divided into two groups, respectively. ADC-8201 and ADC029 were given respectively at the dose of 300 mg/kg, and the body weight was 18.6-21.8 g at the time of administration. The mice were administered by tail vein injection. The body weight of the mice was measured at different time points within 14 days after administration. The results are summarized in the table below. The groups 01 and 02 were given ADC-8201, the groups 03 and 04 were given ADC029, the groups 01 and 03 were male mice, and the groups 02 and 04 were female mice. The test results (shown in Table 13) show that the weight of the mice does not decrease significantly when the dose of ADC029 to mice reached 300 mg/kg, indicating that the ADC has good safety. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 In vivo safety evaluation of ADCs in mice 
               
            
           
           
               
               
            
               
                   
                 Observation days 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Group 
                 0 
                 1 
                 2 
                 3 
                 7 
                 10 
                 14 
               
               
                   
               
            
           
           
               
            
               
                 Weight/g 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 01 
                 20.9 
                 19.8 
                 19.8 
                 20.5 
                 25.2 
                 28.2 
                 32.4 
               
               
                 02 
                 19.8 
                 19.0 
                 18.3 
                 18.7 
                 22.5 
                 23.1 
                 25.3 
               
               
                 03 
                 21.0 
                 20.0 
                 19.7 
                 20.0 
                 25.9 
                 28.8 
                 33.0 
               
               
                 04 
                 19.8 
                 18.5 
                 18.0 
                 18.5 
                 22.0 
                 22.5 
                 25.5 
               
            
           
           
               
            
               
                 Standard deviation 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 01 
                 0.4 
                 0.4 
                 0.6 
                 3.1 
                 4.4 
                 4.7 
                 4.0 
               
               
                 02 
                 0.4 
                 1.2 
                 1.1 
                 0.7 
                 1.7 
                 1.4 
                 3.8 
               
               
                 03 
                 0.4 
                 0.8 
                 0.4 
                 1.2 
                 5.0 
                 3.1 
                 2.4 
               
               
                 04 
                 0.5 
                 2.1 
                 1.7 
                 4.2 
                 1.7 
                 4.1 
                 6.3 
               
               
                   
               
            
           
         
       
     
     Although the specific embodiments of the present disclosure are described above, those skilled in the art should understand that these are only embodiments, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present disclosure. Therefore, the protection scope of the present invention is defined by the appended claims.