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NZ740365B2 - Cd3 binding polypeptides - Google Patents
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NZ740365B2 - Cd3 binding polypeptides - Google Patents

Cd3 binding polypeptides Download PDF

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Publication number
NZ740365B2
NZ740365B2 NZ740365A NZ74036516A NZ740365B2 NZ 740365 B2 NZ740365 B2 NZ 740365B2 NZ 740365 A NZ740365 A NZ 740365A NZ 74036516 A NZ74036516 A NZ 74036516A NZ 740365 B2 NZ740365 B2 NZ 740365B2
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New Zealand
Prior art keywords
binding polypeptide
chain variable
variable region
binding
amino acid
Prior art date
Application number
NZ740365A
Other versions
NZ740365A (en
Inventor
John W Blankenship
Philip Tan
Original Assignee
Aptevo Research And Development Llc
Filing date
Publication date
Application filed by Aptevo Research And Development Llc filed Critical Aptevo Research And Development Llc
Priority claimed from PCT/US2016/052942 external-priority patent/WO2017053469A2/en
Publication of NZ740365A publication Critical patent/NZ740365A/en
Publication of NZ740365B2 publication Critical patent/NZ740365B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

The present disclosure relates to protein molecules that specifically bind to CD3, which may have at least one humanized CD3-binding domain. Such molecules are useful for the treatment of cancer. The protein molecule binding to CD3 may have a second binding domain that binds to another target. In one embodiment, multispecific polypeptide molecules bind both tumor antigen-expressing cells and the CD3 subunit of a T-cell receptor complex on T-cells to induce target-dependent T-cell cytotoxicity, activation, and proliferation. The disclosure also provides pharmaceutical compositions comprising the CD3-binding poypeptide molecules, nucleic acid molecules encoding these polypeptides and methods of making these molecules.

Claims (35)

CLAIMS :
1. A CD3-binding polypeptide comprising a CD3-binding domain that binds specifically to human CD3 and that comprises a humanized immunoglobulin light chain variable region and a humanized immunoglobulin heavy chain variable region; wherein the immunoglobulin light chain variable region comprises an LCDR1amino acid sequence of SEQ ID NO: 94, an LCDR2 amino acid sequence of SEQ ID NO: 95, and an LCDR3 amino acid sequence of SEQ ID NO: 96 and wherein the immunoglobulin heavy chain variable region comprises an HCDR1 amino acid sequence of SEQ ID NO: 91, an HCDR2 amino acid sequence of SEQ ID NO: 92, and an HCDR3 amino acid sequence of SEQ ID NO: 93; wherein the amino acid residue at position 9 according to the IMGT ing system of the immunoglobulin heavy chain variable region is proline; and wherein the amino acid residue at position 21 ing to the IMGT numbering system of the immunoglobulin light chain variable region is methionine; wherein the amino acid residue at position 87 according to the IMGT numbering system of the immunoglobulin light chain le region is ne; and wherein (a) the globulin light chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO:88 and the immunoglobulin heavy chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO:86; or (b) the immunoglobulin light chain variable region comprises an amino acid sequence that is at least 96% identical to SEQ ID NO:89 and the immunoglobulin heavy chain variable region comprises an amino acid sequence that is at least 96% cal to SEQ ID NO:86.
2. The CD3-binding ptide of claim 1, wherein (a) the immunoglobulin light chain variable region comprises SEQ ID NO:88 and the immunoglobulin heavy chain variable region comprises SEQ ID NO:86; or (b) the immunoglobulin light chain variable region comprises SEQ ID NO:89 and the immunoglobulin heavy chain variable region comprises SEQ ID NO:86.
3. The CD3-binding polypeptide of claim 1, n the amino acid e at position 52 according to the IMGT numbering system of the immunoglobulin light chain variable region is arginine and/or the amino acid residue at position 53 according to the IMGT numbering system of the immunoglobulin light chain variable region is tryptophan.
4. The CD3-binding polypeptide of claim 1, wherein the amino acid residue at position 27 ing to the IMGT numbering system of the immunoglobulin heavy chain le region is ne.
5. The CD3-binding polypeptide of claim 1, wherein the amino acid residue at on 53 according to the IMGT numbering system of the immunoglobulin heavy chain variable region is isoleucine.
6. The CD3-binding polypeptide of claim 1, wherein the amino acid residue at position 86 according to the IMGT numbering system of the immunoglobulin light chain variable region is aspartic acid.
7. The CD3-binding ptide of any one of claims 1-6, wherein the CD3-binding domain comprises SEQ ID NO:83 or SEQ ID NO:84.
8. The CD3-binding polypeptide of any one of claims 1-7, wherein the CD3-binding domain is a single chain variable fragment (scFv).
9. The CD3-binding polypeptide of claim 8, wherein said scFv comprises a linker n the heavy chain variable region and the light chain variable region of said scFv and n said linker comprises the amino acid sequence QRHNNSSLNTGTQMAGHSPNS (SEQ ID NO:148).
10. The CD3-binding polypeptide of claim 8, wherein the heavy chain variable region of said scFv is amino-terminal to the light chain variable region of said scFv.
11. The CD3-binding polypeptide of any one of claims 1-10, further comprising a second binding domain.
12. The CD3-binding polypeptide of claim 11, wherein said nding polypeptide comprises, in order from amino-terminus to carboxyl-terminus, (i) the -binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl-terminus linker, and (v) the nding domain.
13. The CD3-binding polypeptide of claim 11 or 12, wherein the second binding domain comprises (a) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and (b) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3.
14. The CD3-binding polypeptide of claim 12 or 13, n the hinge region is derived from an immunoglobulin hinge region.
15. The CD3-binding polypeptide of any one of claims 12-14, wherein the carboxyl-terminus linker comprises or consists of SEQ ID NO:196.
16. The CD3-binding polypeptide of any one of claims 12-15, wherein the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgD.
17. The CD3-binding polypeptide of claim 16, wherein the immunoglobulin constant region comprises a human IgG1 CH2 domain comprising the tutions L234A, L235A, G237A, and K322A, ing to the EU numbering system.
18. The CD3-binding polypeptide of any one of claims 11-17, wherein the CD3-binding polypeptide induces redirected T-cell cytotoxicity (RTCC).
19. The CD3-binding polypeptide of claim 18, wherein the CD3-binding ptide s RTCC with an EC50 of about 30 pM or lower.
20. The CD3-binding polypeptide of any one of claims 11-19, wherein the second binding domain is a single chain variable fragment (scFv).
21. The CD3-binding polypeptide of any one of claims 11-20, wherein the second binding domain binds or interacts with a tumor associated antigen.
22. The CD3-binding polypeptide of claim 21, wherein said CD3-binding polypeptide induces -dependent lysis of cells expressing the tumor associated antigen.
23. The CD3-binding polypeptide of claim 21, wherein the tumor associated antigen is selected from the group consisting of PSMA, CD19, CD20, CD37, CD38, CD123, Her2, ROR1, RON, glycoprotein A33 antigen (gpA33), and CEA..
24. An isolated nucleic acid molecule encoding the CD3-binding polypeptide of any one of claims 1-23 or a n of said CD3-binding polypeptide.
25. An expression vector comprising a nucleic acid segment encoding the nding polypeptide of any one of claims 1-23, n the nucleic acid segment is operatively linked to regulatory ces suitable for expression of the nucleic acid segment in a host cell.
26. An isolated recombinant host cell comprising the expression vector of claim 25.
27. A method for producing a nding polypeptide, the method comprising culturing a recombinant host cell comprising the expression vector of claim 26 under conditions whereby the nucleic acid segment is expressed, thereby producing the CD3-binding polypeptide; and recovering the CD3-binding polypeptide.
28. A pharmaceutical composition comprising the nding polypeptide of any one of claims 1-23, and a pharmaceutically able carrier, diluent, or excipient.
29. Use of the CD3-binding polypeptide of any one of claims 1-23 in the preparation of a medicament, wherein the medicament is to be used in the treatment of a disease or disorder associated with tumor growth, which comprises the step of contacting a tumor associated antigen-expressing cell with the CD3-binding polypeptide of any one of claims 1-24 under ions whereby redirected T-cell cytotoxicity (RTCC) against the tumor associated n-expressing cell is induced.
30. Use of the nding polypeptide of any one of claims 1-23 in the preparation of a medicament for inhibiting tumour growth in a subject in need thereof.
31. Use of the CD3-binding polypeptide of any one of claims 1-23 in the preparation of a ment for the treatment of cancer or an autoimmune disorder in a subject in need thereof.
32. The use of claim 31, wherein the cancer is prostate , colorectal cancer, renal cell carcinoma, r cancer, salivary gland cancer, pancreatic cancer, ovarian cancer, non-small cell lung cancer, breast cancer (e.g., triple negative breast ). melanoma, adrenal cancer, mantle cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), B-lymphoid leukemia, blastic plasmocytoid dendritic neoplasm (BPDCN), or hairy cell ia.
33. The use of claim 32, wherein the breast cancer is triple negative breast cancer.
34. A CD3-binding protein that is a dimer of two identical polypeptides, wherein each polypeptide is the CD3-binding polypeptide of any one of claims 1-23.
35. The CD3-binding polypeptide of any one of claims 1-23, wherein the CD3-binding polypeptide does not exhibit or exhibits minimal antibody-dependent cell-mediated cytotoxicity (ADCC) activity and/or complement-dependent cytotoxicity (CDC) activity. NHMUWF 38? m?mumx imam» xmmum» ?mumx mxmumx ?mmumx a? 1%... xx 5%: xxx Ex: xxx ax... x; , xxx x . mama MEEV manage moo E: “2: E: E: x Md xxxxxx ?mmwmxw?wumau 5% v.0 No «.9 <+ 5: S -1, 4;. QM NV. mmd VIE. me 0m. Eu Nwmomb mwmuwh 33$ ESE. .EéEa£2 wNmUmh mxmxxmm gm @@W gm gm @3 gamma 6&3 ENE Aw?xv “Ema Ang “Ema 63% ESE 5.5% ?g mwmomlm. 33$ ammomw 3ng $8“? mmmowk 38ml“. 33% $8me @mom? 02 wma mmnm §N\vs {New w\\\\\: Q 9 mam...” magma “Exams mcm?mmm A?wxv 56% SEE 6.5% $39, $33 33E. $.83: $83 ??owxvawmuww ngigumw @8me .
NZ740365A 2016-09-21 Cd3 binding polypeptides NZ740365B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562221190P 2015-09-21 2015-09-21
PCT/US2016/052942 WO2017053469A2 (en) 2015-09-21 2016-09-21 Cd3 binding polypeptides

Publications (2)

Publication Number Publication Date
NZ740365A NZ740365A (en) 2024-12-20
NZ740365B2 true NZ740365B2 (en) 2025-03-21

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