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NZ778205B2 - Humanized or chimeric CD3 antibodies - Google Patents

Humanized or chimeric CD3 antibodies

Info

Publication number
NZ778205B2
NZ778205B2 NZ778205A NZ77820516A NZ778205B2 NZ 778205 B2 NZ778205 B2 NZ 778205B2 NZ 778205 A NZ778205 A NZ 778205A NZ 77820516 A NZ77820516 A NZ 77820516A NZ 778205 B2 NZ778205 B2 NZ 778205B2
Authority
NZ
New Zealand
Prior art keywords
seq
set forth
cdr2
antibody
cdr1
Prior art date
Application number
NZ778205A
Other versions
NZ778205A (en
Inventor
Isil Altintas
Patrick Engelberts
Paul Parren
Rik Rademaker
Janine Schuurman
Original Assignee
Genmab A/S
Filing date
Publication date
Priority claimed from PCT/EP2016/050296 external-priority patent/WO2016110576A1/en
Application filed by Genmab A/S filed Critical Genmab A/S
Priority claimed from NZ739028A external-priority patent/NZ739028A/en
Publication of NZ778205A publication Critical patent/NZ778205A/en
Publication of NZ778205B2 publication Critical patent/NZ778205B2/en

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], 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 [IGs], 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 [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4216—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-viral Ig
    • 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
    • C07K2317/50—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
    • C07K2317/55—Fab or Fab'
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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

Abstract

The present invention relates to humanized or chimeric antibodies binding CD3. It furthermore relates to bispecific antibodies, compositions, pharmaceutical compositions, use of said antibodies in the treatment of a disease, and method of treatment.

Claims (28)

Claims
1. A zed or chimeric antibody binding to human CD3, wherein said antibody comprises a binding region comprising: a heavy chain variable (VH) region, wherein said VH region comprises a mutation in one of the three CDR sequences of a reference dy having the CDR sequences set forth in CDR1 SEQ ID NO: 1, CDR2 SEQ ID NO: 2 and CDR3 SEQ ID NO: 3, which mutation is selected from the group consisting of: T31M, T31P, N57E, H101N, S110A, S110G, Y114M, Y114R and Y114V, wherein the positions are numbered according to the reference sequence of SEQ ID NO: 4; and a light chain variable (VL) region, wherein said VL region comprises CDR1, CDR2, and CDR3 regions having the CDR sequences as set forth in SEQ ID NO:6, GTN and 7, respectively.
2. The antibody according to claim 1, wherein said VH region comprises the CDR1, CDR2, and CDR3 sequences selected from the group consisting of; a) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 54, 2, 3 [T31M] ; b) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 58, 2, 3 [T31P]; c) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 106, 3 [N57E]; d) CDR1, CDR2 and CDR3 ces set forth in SEQ ID NO: 1, 2, 184 [H101N]; e) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 236 [S110A]; f) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 244 [S110G]; g) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 284 [Y114M]; h) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 292 [Y114R]; i) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 298 [Y114V].
3. The antibody according to any one of claims 1 to 2, n said VH region has a VH sequence ed from the group consisting of; a) a VH ce as set forth in SEQ ID NO: 55[T31M], b) a VH sequence as set forth in SEQ ID NO: 59 [T31P], c) a VH sequence as set forth in SEQ ID NO: 107 [N57E] d) a VH sequence as set forth in SEQ ID NO: 185 [H101N], e) a VH sequence as set forth in SEQ ID NO: 237 [S110A], f) a VH sequence as set forth in SEQ ID NO: 245 ], g) a VH sequence as set forth in SEQ ID NO: 285 [Y114M], h) a VH sequence as set forth in SEQ ID NO: 293 [Y114R], i) a VH sequence as set forth in SEQ ID NO: 299 [Y114V], and 21633989_1 ters) P43747NZ01 j) a VH sequence having at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to any one of the sequences as set forth in a) to j).
4. The antibody according to any one of the preceding claims, wherein said VL region comprises CDR1, CDR2 and CDR3 regions having the sequences as set forth in SEQ ID NO: 6, GTN and 7, and wherein said VH region comprises CDR1, CDR2, and CDR3 regions having the CDR sequences ed from the group consisting of; a) CDR1, CDR2 and CDR3 ces set forth in SEQ ID NO: 54, 2, 3 [T31M] ; b) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 58, 2, 3 [T31P]; c) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 106, 3 [N57E]; d) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 184 [H101N]; e) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 236 [S110A]; f) CDR1, CDR2 and CDR3 ces set forth in SEQ ID NO: 1, 2, 244 [S110G]; g) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 284 [Y114M]; h) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 292 [Y114R]; i) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 298 ].
5. The antibody according to any one of the preceding claims, wherein human CD3 is human CD3 n as specified in SEQ ID NO: 399.
6. The antibody according to any one of the preceding claims, wherein the antibody is: a humanized antibody; a full-length antibody; of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4; and/or monovalent, bivalent or multivalent.
7. The antibody ing to any one of the preceding claims, wherein said antibody comprises: an Fc region comprising a first and a second immunoglobulin heavy chain; and/or a first and a second immunoglobulin heavy chain, wherein in at least one of said first and second immunoglobulin heavy chains one or more amino acids in the positions corresponding to ons L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively.
8. The antibody according to claim 7, wherein in at least one of said first and second: 21633989_1 (GHMatters) P43747NZ01 immunoglobulin heavy chains the amino acid in the position corresponding to position D265 in a human IgG1 heavy chain, is not D; heavy chains the amino acid in the on corresponding to position N297 in a human IgG1 heavy chain, is not N; heavy chains the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain, are not L and L, respectively; heavy chains the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain, are F and E; or A and A, respectively; heavy chains the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain, are F and E, respectively; heavy chains the amino acids in the positions ponding to positions L234 and L235 in a human IgG1 heavy chain, are A and A, respectively; heavy chains the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, are not L, L, and D, respectively; heavy chains the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, are F, E, and A; or A, A, and A, respectively; heavy chains the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, are F, E, and A, respectively; heavy chains the amino acids in the positions corresponding to ons L234, L235, and D265 in a human IgG1 heavy chain, are A, A, and A, tively; and/or heavy chains the amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain, are F, E, A, Q, and S, respectively.
9. A bispecific antibody comprising a first binding region of an antibody according to any one of the preceding claims, and a second binding region which binds a different target than said first antigen binding region.
10. The ific antibody according to claim 9, wherein said antibody comprises a first and a second heavy chain, and wherein each of said first and second heavy chain comprises at least a hinge , a CH2 and CH3 region, wherein in said first heavy chain at least one of the amino acids in the positions corresponding to a positions selected from the group ting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and in said second heavy chain at least one of the amino acids in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and n said first and said second heavy chains are not substituted in the same positions. 21633989_1 (GHMatters) P43747NZ01
11. The bispecific antibody according to claim 10, wherein the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said first heavy chain, and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said second heavy chain, or vice versa.
12. A method of reducing the binding affinity of an antibody binding to human CD3 compared to a reference antibody comprising a heavy chain variable (VH) region and a light chain le (VL) region, wherein said VH region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 1, 2, 3, which method comprises introducing a mutation in one of the three CDR sequences of the said reference antibody selected from the group of T31M, T31P, N57E, H101N, S110A, S110G, Y114M, Y114R and Y114V, wherein the positions are ed ing to the reference sequence of the SEQ ID NO: 4; and wherein said VL region comprises CDR1, CDR2, and CDR3 regions having the CDR sequences as set forth in SEQ ID NO:6, GTN and 7, respectively.
13. The antibody or method according to any one of the preceding claims, wherein the antibody has a binding affinity to human CD3 epsilon peptide with SEQ ID NO: 402 corresponding to a KD value from 1.0x10-7 to 9.9x10-7 M as determined by Bio-Layer Interferometry.
14. The antibody or method ing to claim 13, wherein the human CD3 epsilon is sed on a T cell or is in isolated form, e.g. an isolated human CD3 epsilonpeptide.
15. A nucleic acid construct encoding one or more pairs of CDRs1-3 or VH and VL amino acid sequences of any of claims 1 to 11.
16. An expression vector comprising (i) a nucleic acid sequence ng a heavy chain sequence of a humanized or chimeric antibody according to any one of claims 1 to 11; and (ii) a nucleic acid sequence ng a light chain sequence of a humanized or chimeric dy according to any one of claims 1 to 11.
17. An isolated and/or non-human host cell comprising an expression vector of claim 21633989_1 ters) P43747NZ01
18. The host cell according to claim 17, wherein said host cell is a recombinant eukaryotic, recombinant prokaryotic, or recombinant microbial host cell.
19. A composition comprising an dy according to any one of claims 1 to 8 or a bispecific antibody according to any one of claims 9 to 11.
20. A pharmaceutical composition sing the antibody according to any one of claims 1 to 8, or the bispecific antibody according to any one of claims 9-11 and a pharmaceutical able carrier.
21. The antibody according to any one of claims 1 to 11, the composition according to claim 19, or the pharmaceutical composition according to claim 20 for use as a medicament; for use as a medicament in treating cancer, an infectious e, or autoimmune diseases; and/or for use in treating a disease.
22. Use of the antibody according to any one of claims 1 to 8, or the bispecific antibody according to any one of claims 9-11, in the preparation of a medicament for treating a disease in a subject.
23. Use of the antibody according to claim 22, wherein the subject is determined by detecting the ce or absence of a complex formed between the antibody according to any one of claims 1 to 8, or the bispecific dy ing to any one of claims 9-11, and CD3, optionally wherein said antibody is labeled with a detectable agent.
24. The use according to claim 23, wherein the disease is cancer, an ious disease, or an mune disease.
25. A method for producing an antibody according to any one of claims 1 to 11 comprising the steps of a) culturing a host cell according to claim 17 or 18; and b) purifying said antibody from the culture media.
26. A diagnostic composition comprising an antibody according to any one of claims 1 to 8 or a bispecific antibody according to any one of claims 9 to 11.
27. A method for detecting the presence of CD3 antigen, or a cell expressing CD3, in a sample comprising the steps of; 21633989_1 (GHMatters) P43747NZ01 a) contacting the sample with an antibody according to any one of claims 1 to 8 or a ific antibody according to any one of claims 9 to 11, under conditions that allow for formation of a complex between said antibody or bispecific antibody and CD3; and b) analyzing whether a complex has been formed.
28. A kit for detecting the presence of CD3 antigen, or a cell sing CD3, in a sample comprising i) an antibody according to any one of claims 1 to 8 or a bispecific dy according to any one of claims 9 to 11; and ii) instructions for use of said kit. 21633989_1 (GHMatters) P43747NZ01 1/ 13
NZ778205A 2016-07-14 Humanized or chimeric CD3 antibodies NZ778205B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DKPA201500413 2015-07-15
DKPA201500414 2015-07-15
DKPA201500416 2015-07-16
PCT/EP2016/050296 WO2016110576A1 (en) 2015-01-08 2016-01-08 Bispecific antibodies against cd3 and cd20
NZ739028A NZ739028A (en) 2015-07-15 2016-07-14 Humanized or chimeric cd3 antibodies

Publications (2)

Publication Number Publication Date
NZ778205A NZ778205A (en) 2025-05-02
NZ778205B2 true NZ778205B2 (en) 2025-08-05

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