Patent application EP19382371A (EP), filed 2019-05-13
Publication number: EP3738614A1
Title: METHODS FOR PRODUCING HOMOGENEOUS ANTIBODY DRUG CONJUGATES
Abstract: A method is provided for producing antibody conjugates having homogeneous payload antibody ratio. The method comprises: (i) providing separate fractions of heavy chains and light chains of an antibody or a fragment thereof both having interchain thiols; (ii) separately conjugating a payload to the interchain thiols of the heavy chains or to the interchain thiols of the light chains or to both; and (iii) assembling the resulting heavy chains with the resulting light chains by mixing them to form antibody conjugates. A homogeneous composition is obtained comprising antibody conjugates of the same payload antibody ratio, wherein the antibody in the antibody conjugate has its native amino acid sequence without modifications and with the sugar groups of the original antibody.
IPC codes: A61K  47/    68            A I
Claims: number: 1
text: A method for producing antibody conjugates having homogeneous payload antibody ratio, the method comprising:
number: 2
text: The method for producing antibody conjugates according to claim 1, wherein the step (i) of providing separate fractions of heavy chains and light chains is performed by a method selected from:
number: 3
text: The method for producing antibody conjugates according to claim 1, wherein the resulting antibody conjugates are homogeneous with a payload antibody ratio of 2 and wherein a payload is conjugated to the interchain thiols of the light chains, the method comprising:
number: 4
text: The method for producing antibody conjugates according to claim 1, wherein the resulting antibody conjugates are homogeneous with a payload antibody ratio of 2 and wherein a payload is conjugated to the Fab domain interchain thiols of the heavy chains, the method comprising:
number: 5
text: The method for producing antibody conjugates according to claim 1, wherein the resulting antibody conjugates are homogeneous with a payload antibody ratio of 4 and wherein a payload is conjugated to the Fab domain interchain thiols of the heavy chains and a payload is conjugated to the interchain thiols of the light chains, the method comprising:
number: 6
text: The method for producing antibody conjugates according to claim 1, wherein the resulting antibody conjugates are homogeneous with a payload antibody ratio of 8 and wherein a payload is conjugated to interchain thiols of the heavy chains and a payload is conjugated to the interchain thiols of the light chains, the method comprising:
number: 7
text: The method for producing antibody conjugates according to any of claims 3, 5 and 6, wherein the step of providing light chains and/or heavy chains with free interchain thiols, comprises the steps of:
number: 8
text: The method for producing antibody conjugates according to any of claims 4-5, wherein the step of providing heavy chain dimers with interchain disulfide bonds between the monomers, and with the Fab domain interchain thiols in free form, comprises the steps of:
number: 9
text: The method for producing antibody conjugates according to any of claims 1-8, wherein the payload is selected from the group consisting of a drug, an oligonucleotide, a peptide, an enzyme, a protein, a substrate, an inorganic compound, a chelate, a radioactive agent, a detectable reagent, and a nanoparticle.
number: 10
text: The method for producing antibody conjugates according to any of claims 1-9, wherein the separate fractions of heavy chains and light chains are obtained by a method comprising:
number: 11
text: A homogeneous composition obtainable by any of the methods as defined in claims 1-10, comprising antibody conjugates of the same payload antibody ratio, wherein the antibody in the antibody conjugate has its native amino acid sequence without modifications.
number: 12
text: The homogeneous composition according to claim 11, wherein the antibody conjugates have a payload antibody ratio of 2 and the payload is conjugated to the Fab domain interchain thiols of the heavy chains or of the light chains.
number: 13
text: The homogeneous composition according to claim 11, wherein the antibody conjugates have a payload antibody ratio of 4 and the payload is conjugated to both the Fab domain interchain thiols of the heavy chains and the light chains.
number: 14
text: The homogeneous antibody conjugates according to claim 13, wherein the payload conjugated to the light chains is different from the payload conjugated to the heavy chains.
number: 15
text: The homogeneous composition according to any of claims 12-13, wherein the antibody is trastuzumab and the payload is monomethyl auristatin E linked via a valine-citrulline dipeptide.
Office action: search_report, dated 2020-11-18
Rejection reasons: novelty_epc_54
inventive_step_epc_56
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severity: background
ref_id: WO2005084390
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severity: novelty_destroying
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ref_type: npl
severity: novelty_destroying
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ref_type: npl
severity: novelty_destroying
ref_id: - MALIN KÄLLSTEN ET AL, "Qualitative analysis of antibody-drug conjugates (ADCs): an experimental comparison of analytical techniques of cysteine-linked ADCs", ANALYST, UK, (20180101), vol. 143, no. 22, doi:10.1039/C8AN01178H, ISSN 0003-2654, pages 5487 - 5496, XP055641580 [Y] 1-15 * page 5488, "Samples" * * figures 1,2 * * table 1 *
ref_type: npl
severity: obviousness
ref_id: - MEGHDAD ABDOLLAHPOUR-ALITAPPEH ET AL, "Trastuzumab-monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2-positive human breast cancer", JOURNAL OF CELLULAR PHYSIOLOGY, US, (20181129), vol. 234, no. 3, doi:10.1002/jcp.27085, ISSN 0021-9541, pages 2693 - 2704, XP055612296 [Y] 1-15 * abstract * * figure 7 * * page  2701, column  left * * page  2702, column  left, paragraph  last  - column  right, line  2 * * page 2695, section 2.3 "Conjugate preparation" *
ref_type: npl
severity: obviousness
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ref_type: npl
severity: obviousness
Final disposition: pending (2020-11-18)