Office Action 2: Notice of Allowance (2025-01-10)

CLAIMS:
Amendments to the Claims:

The following listing of claims will replace all prior versions and listings of claims in the case.

1\. (Currently Amended) A vector, comprising:a polynucleotide comprising one or more transcriptional units, wherein each of the one or more transcriptional units is operatively linked to a promoter active in T cells, and wherein the one or more transcriptional units encode:
i. a first engineered signaling polypeptide, wherein said first engineered signaling polypeptide is a chimeric polypeptide comprising an extracellular domain, a transmembrane domain, and a first intracellular signaling domain capable of activating a cellular signaling pathway, wherein said transmembrane domain is covalently attached to said extracellular domain and said first intracellular signaling domain,
wherein said transmembrane domain is between 15 and 100 amino acids,
wherein said first intracellular signaling domain comprises an intracellular signaling domain that comprises a first ITAM motif, wherein the first ITAM motif comprises the sequence YX1X2L/I, wherein Xi is any amino acid and X2 is any amino acid,
wherein said first intracellular signaling domain is selected from CD79A having at least 90% sequence identity to the sequence of SEQ ID NO:210 and CD79B having at least 90% sequence identity to the sequence of SEQ ID NO:211, and
wherein said extracellular domain comprises a leucine zipper dimerizing motif, and
ii. a second engineered signaling polypeptide comprising a chimeric antigen receptor (CAR) or a recombinant TCR.

2\. (Original) The vector of claim 1, wherein the leucine zipper dimerizing motif is from a jun polypeptide.

3\. (Original) The vector of claim 1, wherein a linker of between 1 and 4 alanine residues is present between the extracellular domain and the transmembrane domain.

4\. (Original) The vector of claim 1, wherein the first intracellular signaling domain comprises a second ITAM motif.

5\. (Previously Presented) The vector of claim 1, wherein:the first intracellular signaling domain comprises the intracellular signaling domain from CD79A and the transmembrane domain does not comprise a transmembrane domain from CD79A, or the first intracellular signaling domain comprises the intracellular signaling domain from CD79B and the transmembrane domain does not comprise a transmembrane domain from CD79B.

6\. (Previously Presented) The vector of claim 1, wherein:the first intracellular signaling domain comprises the intracellular signaling domain from CD79A and comprises the tyrosine residue corresponding to Y4 and/or Y15 of SEQ ID NO:42, or the first intracellular signaling domain comprises the intracellular signaling domain from CD79B and comprises the tyrosine residue corresponding to Y16 and/or Y27 of SEQ ID NO:211.

7-10. (Canceled)89

11\. (Previously Presented) The vector of claim 6, wherein the intracellular signaling domain from CD79A is at least 95% identical to the sequence of SEQ ID NO:210, or the intracellular signaling domain from CD79B is at least 95% identical to the sequence of SEQ ID NO:211.

12\. (Canceled)

13\. (Previously Presented) The vector of claim 1, wherein the first engineered signaling polypeptide comprises a second intracellular signaling domain, and wherein:the first intracellular signaling domain comprises the intracellular signaling domain from CD79A and the second intracellular signaling domain does not comprise an intracellular signaling domain from CD79A, or

the first intracellular signaling domain comprises the intracellular signaling domain from CD79B and the second intracellular signaling domain does not comprise an intracellular signaling domain from CD79B.

14\. (Previously Presented) The vector of claim 13, wherein the first intracellular signaling domain comprises the intracellular signaling domain from CD79A, and wherein the second intracellular signaling domain is capable of activating a cellular signaling pathway and is 90% identical to an intracellular signaling domain from a gene selected from CSF3R, IL3RA, IL10RB, IL11RA, IL17RB, IL17RC, and IL23R.

15\. (Previously Presented) The vector of claim 13, wherein the first intracellular signaling domain comprises the intracellular signaling domain from CD79B, and wherein the second intracellular signaling domain is capable of activating a cellular signaling pathway and is 90% identical to an intracellular signaling domain from a gene selected from CSF2RA, CSF3R, EPOR, IFNAR2, IL1R1, IL6ST, IL9R, IL12RB2, IL23R, MPL, MyD88, and OSMR.

16\. (Previously Presented) The vector of claim 1, wherein the first engineered signaling polypeptide is a fusion polypeptide, wherein the fusion polypeptide further comprises a recognition domain that is recognized by a monoclonal antibody approved biologic.

17\. (Original) The vector of claim 1, wherein the vector is a replication incompetent recombinant retroviral particle.

18\. (Original) The replication incompetent recombinant retroviral particle of claim 17, wherein the replication incompetent recombinant retroviral particle is a lentivirus.

19\. (Currently Amended) The replication incompetent recombinant retroviral particle of claim 17, wherein the replication incompetent recombinant retroviral particle further comprises a T cell

activation element, and wherein the T cell activation element comprises a means for binding to CD3.

20\. (Currently Amended) The replication incompetent recombinant retroviral particle of claim 19, wherein the means for binding to CD3 is anti-CD3 antibody, wherein the T cell activation element is fused to a heterologous membrane attachment sequence, and wherein the heterologous membrane attachment sequence is a GPI anchor attachment sequence.

21\. (Previously Presented) The replication incompetent recombinant retroviral particle of claim 17, wherein the replication incompetent recombinant retroviral particle further comprises a heterologous viral envelope protein.

22\. (Original) The replication incompetent recombinant retroviral particle of claim 17, wherein the replication incompetent recombinant retroviral particle further comprises a heterologous viral envelope protein fused to an anti-CD3 antibody.

23\. (Original) The replication incompetent recombinant retroviral particle of claim 17, wherein the first engineered signaling polypeptide is encoded in a reverse orientation with respect to a cis-acting RNA packaging element of the vector.

24\. (Original) The replication incompetent recombinant retroviral particle of claim 17, wherein the first engineered signaling polypeptide possesses the property of:a) improving expansion of pre-activated PBMCs transduced with a retroviral particle comprising a nucleic acid construct encoding the first engineered signaling polypeptide when transduced along with a nucleic acid encoding an anti-CD19 CAR comprising a CD3 zeta intracellular activating domain but no co- stimulatory domain, between day 7 and day 21 of in vitro culturing in the absence of exogenously added cytokines, compared to a control construct identical to the nucleic acid construct comprising the first engineered signaling polypeptide but without the first engineered signaling polypeptide, under identical

conditions; and/or b) expanding pre-activated PBMCs transduced with a nucleic acid construct encoding the first engineered signaling polypeptide at least 2-fold between day 7 and day 21 of in vitro culturing in the absence of exogenously added cytokines, when transduced along with a nucleic acid encoding an anti- CD19 CAR comprising a CD3 zeta intracellular activating domain but no costimulatory domain.

25\. (Previously Presented) The replication incompetent recombinant retroviral particle of claim 17, wherein the replication incompetent recombinant retroviral particle further comprises a membrane-bound cytokine on the surface of the replication incompetent recombinant retroviral particle, wherein the membrane-bound cytokine comprises a fusion polypeptide of IL-7 and DAF, and wherein the fusion polypeptide comprises the amino acid sequence of SEQ ID NO:462.

26\. (Original) A method for genetically modifying a T cell of a subject, wherein the method comprises:contacting a population of T cells comprising the T cell ex vivo, with a population of replication incompetent recombinant retroviral particles according to claim 19, wherein said contacting is performed for less than 12 hours to facilitate membrane fusion of the T cell to the replication incompetent recombinant retroviral particle, thereby genetically modifying the T cell.

27\. (Original) The method of claim 26, wherein the method further comprises:collecting blood comprising the population of T cells from a subject before contacting the population of T cells ex vivo with the population of replication incompetent recombinant retroviral particles; and
reintroducing the genetically modified T cell into the subject.

28\. (Canceled)

29\. (Original) The method of claim 26, wherein the population of T cells comprises between 90% and 100% resting T cells.

30\. (Original) The method of claim 27, wherein the population of T cells undergoes 4 or fewer cell divisions ex vivo prior to being reintroduced into the subject.

31\. (Canceled)

32\. (New) The vector of claim 1, wherein the first intracellular signaling domain is CD79A having at least 90% sequence identity to the sequence of SEQ ID NO:210, wherein the first intracellular signaling domain comprises a domain with at least 90% sequence identity to the sequence of SEQ ID NO:42.

33\. (New) The vector of claim 1, wherein the first intracellular signaling domain is CD79B having at least 90% sequence identity to the sequence of SEQ ID NO:210, wherein the first intracellular signaling domain comprises a domain with at least 90% sequence identity to amino acids 16-30 of SEQ ID NO:211.

OFFICE ACTION:
EXAMINER'S AMENDMENT
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
The application has been amended as follows:
In the claims;
33. (Currently Amended) The vector of claim 1, wherein the first intracellular signaling domain is CD79B having at least 90% sequence identity to the sequence of SEQ ID NO:211, wherein the first intracellular signaling domain comprises a domain with at least 90% sequence identity to amino acids 16-30 of SEQ ID NO:211.
Claim Rejections - 35 USC § 112
The rejection of the claims as lacking written description is withdrawn in light of amendment of the claims and applicant’s remarks.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance: the relevant prior art does not teach or reasonably suggest the claimed vectors comprising two signaling polypeptides wherein the leucine sipper-based polypeptide comprises a signaling domain comprising an ITAM of SEQ ID NO: 210 or SEQ ID NO: 211.  Although the proteins these ITAMs were derived from (CD79A, CD79B) were known in the art, the use of these ITAM motifs in the claimed signaling polypeptide is considered to be unpredictable.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

APPLICANT REBUTTAL: Rem
arks
/Argum
ents
I.
STATUS OF THE CLAIMS
Claims 1-6, 11, 13-27 and 29-30 were pending before this amendment. After entry of this amendment, claims 1-6, 11, 13-27, 29-30, and 32-33 will be pending. Claims 7-10, 12, 28, and 31 were previously canceled. Claims 1 and 19-20 have been amended herein without prejudice or disclaimer to pursuing the subject matter of the previously pending claims in an application claiming priority from the present application. Claims 32 and 33 have been added. Support for the claims can be found throughout the application-as-filed, for example: for claim 1, paragraph [0168]; for claim 19, paragraphs [0347]- [0348]; for claim 20, paragraphs [0347]-[0348]; for claim 32, paragraphs [0179] and [0310]; and for claim 33, paragraphs [0282] and [0310]. No new matter has been added.
II.
INFORMATION DISCLOSURE STATEMENT
Applicant is submitting herewith an information disclosure statement.
III.
PRIORITY
The Office Action states "the instant claims are afforded a priority dated of 3/3/2018." However, there are no rejections in the Office Action based on prior art, and thus the priority dates are not relevant for the instant Office Action or this Response. Thus, Applicant neither confirms nor denies the priority dates asserted in the Office Action.
IV.
35 U.S.C.
112(a)
Claims 1-6, 11, 13-27, and 29-30 stand rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement for allegedly containing subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed had possession of the claimed invention. The Office Action asserts:
The claims encompass vectors and retroviral particles comprising CD79 intracellular signaling domains "with 90% sequence identity" to SEQ ID NOs 210
or 211, e.g. as recited in claim 1. According to the definitions in the specification, this element can be any domain with the recited functions of intracellular signaling and activating a T cell. Thus, the claims encompass a very broad genus of
substitutions, mutations, deletions, and insertions of the CD79 protein domains.
However, applicant was not in possession of the claimed genera of CD79 intracellular signaling domains with signaling activity as elements of the claimed products in the absence of providing sufficient structural and functional characteristics of the genera of each of these elements broadly encompassed by the instant claim language, coupled with a known or disclosed correlation between
function and structure.
Without acquiescing to the rejection, and solely in an effort to expedite prosecution, claim 1 has been amended to recite "wherein the first ITAM motif comprises the sequence YX1X2L/I, wherein X1 is any amino acid and X2 is any amino acid". The sequence of the ITAM motif provides additional structure to the first intracellular signaling domain, and the ITAM motif has a known correlation between function and structure (see, e.g., Isakov. Role of immunoreceptor tyrosine-based activation motif in signal transduction from antigen and Fc receptors. Adv Immunol. 1998:69:183-247). Thus, claim 1 and claims 2- 6, 11, 13-27, 29-30, and 32-33 dependent therefrom are described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed had possession of the claimed invention. Applicant respectfully requests withdrawal of the rejections of claims 1-6, 11, 13-27, and 29-30 under 35 U.S.C. 112(a).
Conclusion


CITED REFERENCE SUMMARIES: Ref WO2022047417A1: Claims:
A polynucleotide, comprising: one or more transcriptional units, wherein each of the one or more transcriptional units is operatively linked to a promoter active in T cells and/or NK cells, wherein the one or more transcriptional units comprise: a) nucleic acids encoding a first engineered signaling polypeptide, wherein the first engineered signaling polypeptide is a chimeric antigen receptor (CAR), and b) nucleic acids encoding an anti-idiotype polypeptide comprising an anti-idiotype extracellular recognition domain, a membrane association domain, and a stalk that connects the anti-idiotype extracellular recognition domain to the membrane association domain, wherein the anti-idiotype extracellular recognition domain comprises an idiotype-binding variable region of an anti-idiotype antibody or antibody mimetic that recognizes the idiotype of a target antibody or a target antibody mimetic.
A modified mammalian cell, comprising the polynucleotide of claim 1.
A method for delivering modified T cells and/or NK cells to a subject, wherein the method comprises administering the modified T cells and/or NK cells to the subject, wherein the modified T cells and/or NK cells comprise the polynucleotide of claim 1.
Use of modified T cells and/or NK cells in the manufacture of a kit, wherein the use of the kit comprises: administering the modified T cells and/or NK cells to a subject, wherein the modified T cells and/or NK cells comprise the polynucleotide of claim 1.
A polynucleotide vector, comprising the polynucleotide of claim 1.
A polypeptide, comprising an extracellular recognition domain, a membrane association domain, and a stalk connecting the extracellular recognition domain to the membrane association domain, and further comprising an intracellular domain (ICD) of a first engineered signaling polypeptide, wherein the first engineered signaling polypeptide is a chimeric antigen receptor (CAR), a recombinant T cell receptor (TCR), or a lymphoproliferative element (LE), and wherein the extracellular recognition domain is an anti-idiotype extracellular recognition domain that recognizes an idiotype of a target antibody.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the anti-idiotype extracellular recognition domain is an antibody comprising an scFv.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the idiotype-binding variable region comprises a framework region, and wherein the framework region is a human framework region.
The modified mammalian cell of claim 2, wherein the cell is one of a population of human cells within an infusion bag.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, or the polynucleotide vector of claim 5, wherein the polynucleotide further encodes a second engineered signaling polypeptide, and wherein the second engineered signaling polypeptide is a lymphoproliferative element.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 10, wherein the lymphoproliferative element comprises an intracellular domain that is a means for transmitting a signal that promotes proliferation or survival of a T cell and/or NK cell.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 11, wherein the lymphoproliferative element is constitutively active.
The polynucleotide, the cell, the method, the use, or the polynucleotide vector of claim 10, wherein the polynucleotide comprises an internal ribosome entry site (IRES), a ribosomal skip sequence and/or cleavage signal, between nucleic acids encoding the first engineered signaling polypeptide or the second engineered signaling polypeptide, and nucleic acids encoding the anti-idiotype polypeptide.
The polynucleotide, the cell, the method, the use, or the polynucleotide vector of claim 10, wherein the polynucleotide comprises an internal ribosome entry site (IRES), a ribosomal skip sequence and/or cleavage signal, between nucleic acids encoding the second engineered signaling polypeptide, and nucleic acids encoding the anti-idiotype polypeptide.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the target antibody comprises an antigen-binding site, and wherein the anti-idiotype polypeptide is capable of binding to the antigenbinding site of the target antibody.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 15, wherein the target antibody or target antibody mimetic is an approved biologic antibody or antibody mimetic, approved by the Food And Drug Administration of the U.S. (USFDA), European Medicines Agency (EMA), National Medical Products Administration of China (NMPA) (Chinese FDA), or the Pharmaceutical and Food Safety Bureau (PFSB) of Japan.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 16, wherein the approved biologic antibody or antibody mimetic is the approved biologic antibody, and wherein the approved biologic antibody is cetuximab, muromonab-CD3, efalizumab, tositumomab- il31, nebacumab, edrecolomab, catumaxomab, daclizumab, olaratumab, abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, adalimumab, ibritumomab tiuxetan, omalizumab, bevacizumab, natalizumab, panitumumab, ranibizumab, eculizumab, certolizumab pegol, ustekinumab, canakinumab, golimumab, ofatumumab, tocilizumab, denosumab, belimumab, ipilimumab, brentuximab vedotin, pertuzumab, ado-trastuzumab emtansine, raxibacumab, obinutuzumab, siltuximab, ramucirumab, vedolizumab, nivolumab, pembrolizumab, blinatumomab, alemtuzumab, evolocumab, idarucizumab, necitumumab, dinutuximab, secukinumab, mepolizumab, alirocumab, daratumumab, elotuzumab, ixekizumab, reslizumab, bezlotoxumab, atezolizumab, obiltoxaximab, brodalumab, dupilumab, inotuzumab ozogamicin, guselkumab, sarilumab, avelumab, emicizumab, ocrelizumab, benralizumab, durvalumab, gemtuzumab ozogamicin, erenumab (erenumab-aooe), galcanezumab (galcanezumab-gnlm), burosumab (burosumab-twza), lanadelumab (lanadelumab-flyo), mogamulizumab (mogamulizumab- kpkc), tildrakizumab (tildrakizumab-asmn), fremanezumab (fremanezumab-vfrm), ravulizumab (ravulizumab-cwvz), cemiplimab (cemiplimab-rwlc), ibalizumab (ibalizumab-uiyk) emapalumab (emapalumab-lzsg), moxetumomab pasudotox (moxetumomab pasudotox-tdfk), caplacizumab (caplacizumab-yhdp), risankizumab (risankizumab-rzaa), polatuzumab vedotin (polatuzumab vedotin- piiq), romosozumab (romosozumab-aqqg), brolucizumab (brolucizumab-dbll), crizanlizumab (crizanlizumab-tmca), enfortumab vedotin (enfortumab vedotin-ejfv), [fam-] trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki), teprotumumab (teprotumumab-trbw), eptinezumab (eptinezumab- jjmr), isatuximab (isatuximab-irfc), sacituzumab govitecan (sacituzumab govitecan-hziy), inebilizumab (inebilizumab-cdon), tafasitamab (tafasitamab-cxix), belantamab mafodotin (belantamab mafodotin- 

blmf), satralizumab (satralizumab-mwge), atoltivimab, maftivimab, odesivimab-ebgn, naxitamab-gqgk, margetuximab-cmkb, ansuvimab-zykl, evinacumab, dostarlimab (dostarlimab-gxly), loncastuximab tesirine (loncastuximab tesirine-lpyl), amivantamab (amivantamab-vmjw), aducanumab (aducanumab- avwa), tralokinumab, anifrolumab (anifrolumab-fnia), oportuzumab monatox, tisotumab vedotin, bimekizumab, narsoplimab, tezepelumab, sintilimab, inolimomb, balstilimab, ublituximab, toripalimab, omburtamab, penpulimab, tanezumab, faricimab, sutimlimab, teplizumab, and retifanlimab.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 16, wherein the anti-idiotype polypeptide comprises a means for binding an idiotype of cetuximab.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 17, wherein the approved biologic antibody is cetuximab.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 19, wherein the anti-idiotype polypeptide is capable of blocking binding of cetuximab to epidermal growth factor receptor.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, or the polynucleotide vector of claim 5, wherein the anti-idiotype polypeptide further comprises one or more intracellular domains (ICD).
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 21, wherein the ICD is between 1 and 35 amino acids in length.
The polynucleotide, the cell, the method, the use, the polynucleotide vector of claim 21, or the polypeptide of claim 6, wherein the membrane association domain is a transmembrane domain.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 23, wherein the ICD comprises all or part of an intracellular signaling domain of one or more lymphoproliferative elements, and wherein the ICD is capable of activating a signaling pathway.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 24, wherein the lymphoproliferative element is inducible, and wherein the inducible 

lymphoproliferative element is capable of activating a proliferative or survival signaling after binding of the anti-idiotype polypeptide to the target antibody or target antibody mimetic.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 25, wherein the ICD is capable upon dimerization, of activating a Jak pathway, a TRAF pathway, a PI3K pathway, and/or a PLC pathway.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 25, wherein the idiotype is present on two target antibodies, a first target antibody, which promotes cytotoxicity, and a second target antibody, which promote less cytotoxicity than the first target antibody.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 24, wherein the one or more cytokine receptors are selected from CD27, CD40, CRLF2, CSF2RA, CSF2RB, CSF3R, EPOR, GHR, IFNAR1, IFNAR2, IFNGR1, IFNGR2, IFNLR1, IL1R1, IL1RAP, IL1RL1, IL1RL2, IL2R, IL2RA, IL2RB, IL2RG, IL3RA, IL4R, IL5RA, IL6R, IL6ST, IL7R, IL7RA, IL9R, IL10RA, IL10RB, IL11RA, IL12RB1, IL13R, IL13RA1, IL13RA2, IL15R, IL15RA, IL17RA, IL17RB, IL17RC, IL17RE, IL18R1, IL18RAP, IL20RA, IL20RB, IL21R, IL22RA1, IL23R, IL27R, IL27RA, IL31RA, LEPR, LIFR, MPL, OSMR, PRLR, TGF R, TGF(3 decoy receptor, TNFRSF4, TNFRSF8, TNFRSF9, TNFRSF14, or TNFRSF18.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 23, wherein the membrane association domain is the transmembrane domain of the lymphoproliferative element, the CAR, or the recombinant TCR.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the stalk is between 4 and 100 amino acids in length.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 30, wherein the stalk encodes a dimerizing moiety, wherein the dimerizing moiety is constitutively dimerized.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 31, wherein the constitutively dimerized dimerization domain comprises a leucine zipper.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, or the polynucleotide vector of claim 5, wherein the polynucleotide further comprises nucleic acids that encode one or more inhibitory RNA molecules.
The polynucleotide, the cell, the method, the use, or the polynucleotide vector of claim 33, wherein the one of the one or more inhibitory RNA molecules targets IFNgamma.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the target antibody is structured such that binding of the anti-idiotype polypeptide to the target antibody induces cytotoxicity.
The method of claim 3, or the use of claim 4, further comprising instructing a user to deliver the target antibody to the subject if treatment for adverse events in the subject is warranted.
The modified mammalian cell of claim 2, wherein the modified mammalian cell is a CAR-T cell or a CAR-NK cell.
A population of modified mammalian cells of claim 2, wherein the population comprises CAR-T cells, CAR-NK cells, or both CAR-T cells and CAR-NK cells.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 23, wherein the ICD comprises an intracellular apoptosis domain capable of inducing an apoptotic signal upon binding of the anti-idiotype extracellular recognition domain to a target antibody or antibody mimetic comprising the idiotype.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 39, wherein the anti-idiotype polypeptide further comprises a proteolytic cleavage site as part of and/or between the transmembrane domain and the intracellular apoptosis domain, wherein the proteolytic cleavage site has a cleavage site amino acid sequence such that the anti-idiotype polypeptide is cleaved at the proteolytic cleavage site when the anti-idiotype polypeptide is dimerized by binding of a target antibody or antibody mimetic to the anti-idiotype extracellular recognition domain.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 40, wherein the proteolytic cleavage site is effective for cleavage by a gamma-secretase complex or a Notch receptor upon dimerization of the anti-idiotype polypeptide.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 41, wherein the intracellular apoptosis domain comprises one or more of a Caspase 2 polypeptide, a Caspase 8 polypeptide, a Caspase 9 polypeptide, and a Caspase 10 polypeptide, wherein such intracellular apoptosis domain is capable of activating an effector caspase upon cleavage from the anti-idiotype polypeptide.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 41, wherein the intracellular apoptosis domain comprises one or more caspase polypeptides, wherein the caspase polypeptides are amino acids 327 to 452 of SEQ ID NO:680 (Caspase 2), amino acids 384 to 496 of SEQ ID NO:681 (Caspase 8), amino acids 294 to 416 of SEQ ID NO:682 (Caspase 9), and amino acids 365 to 478 of SEQ ID NO:683 (Caspase 10).
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 39, wherein the ICD comprises one or more caspase activation and recruitment domains (CARDs), death domains (DDs), death effector domains (DEDs), pyrin domains (PYDs), and/or caspase proteolytic domains that are activate to transmit an apoptosis-inducing signal upon dimerization.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 39, wherein the anti-idiotype polypeptide further comprises a dimerizing moiety, wherein the dimerizing moiety is constitutively dimerized, and/or wherein the target antibody is an IgA or IgM antibody.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 45, wherein the intracellular apoptosis domain comprises one or more death domains (DD) from FAS, TNF-R1, DR3, DR4, and/or DR5.
The vector of claim 5, wherein the vector is a viral vector, and wherein the viral vector is replication incompetent.
The vector of claim 47, wherein the viral vector is a retroviral particle.
The vector of claim 48, wherein the surface of the retroviral particle comprises a membrane-bound cytokine.
The vector of claim 49, wherein the membrane-bound cytokine is a chemokine.
The vector of claim 50, wherein the vector comprises a cleavage signal effective for cleaving the membrane-bound cytokine from the membrane.
The vector of claim 48, wherein the retroviral particle is a lentiviral vector.
The vector of claim 47, further comprising an activation element on the surface of the retroviral particle, wherein the activation element is fused to a heterologous membrane attachment sequence, and wherein the activation element is a polypeptide capable of binding to CD3 on the surface of a resting T cell and activating the resting T cell, and wherein the activation element is not encoded by a polynucleotide in the retroviral particle.
The vector of claim 53, wherein the activation element comprises an anti-CD3 antibody or antibody mimetic.
The polynucleotide of claim 1, the cell of claim 2, the method of claim 3, the use of claim 4, the polynucleotide vector of claim 5, or the polypeptide of claim 6, wherein the anti-idiotype polypeptide comprises the stalk, membrane association domain, and ICD of SEQ ID NO: 676, SEQ ID NO: 677, SEQ ID NO: 678, or SEQ ID NO: 679.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 29, wherein the transmembrane domain is the transmembrane domain of the CAR and the ICD is the ICD of a CAR.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 56, wherein the CAR is a bispecific CAR, wherein the first ASTR of the CAR comprises the antiidiotype extracellular recognition domain.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 57, wherein the second ASTR of the CAR is capable of binding to a tumor-associated antigen or tumor-specific antigen.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 58, wherein the first ASTR and the second ASTR of the CAR are scFv antibodies.
The polynucleotide, the cell, the method, the use, the polynucleotide vector, or the polypeptide of claim 59, wherein the first ASTR and the second ASTR of the CAR comprise an scFv-Fc, scFv-CH, and scFv-zipper antibody.
A retroviral particle, comprising a) a polynucleotide comprising nucleic acids encoding an anti-idiotype polypeptide comprising an anti-idiotype extracellular recognition domain, a membrane association domain, and a stalk that connects the anti-idiotype extracellular recognition domain to the membrane association domain, wherein the antiidiotype extracellular recognition domain comprises an idiotype-binding variable region of an antiidiotype antibody or antibody mimetic that recognizes the idiotype of a target antibody or a target antibody mimetic; and b) an activation element on the surface of the retroviral particle, wherein the activation element is fused to a heterologous membrane attachment sequence, and wherein the activation element is a polypeptide capable of binding to CD3 on the surface of a T cell.
A method for delivering modified T cells and/or NK cells to a subject, the method comprising administering the modified cells to the subject, wherein the modified cells are modified with a polynucleotide comprising nucleic acids encoding an anti-idiotype polypeptide and nucleic acids encoding a CAR.
Use of modified T cells and/or NK cells in the manufacture of a kit, wherein the use of the kit comprises: administering the modified T cells and/or NK cells to a subject, wherein the modified T cells and/or NK cells comprise 
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