Human CD3 binding antibody
The invention is among others concerned with human CD3 binding antibodies comprising a heavy chain and light chain wherein said heavy chain comprises a variable region that comprises the amino acid sequence (SEQ ID NO: 61): QVQLV QSGGG VVQPG RSLRL SCVAS GFTFS SYGMH WVRQA PGKGL EWVAA IWYX 1 X 2 RKQDY ADSVK GRFTI SRDNS KNTLY LQMNS LRAED TAVYY CTRGT GYNWF DPWGQ GTLVT VSS with 0-5 amino acid insertions, deletions, substitutions, additions or a combination thereof at one or more positions other than the position indicated by X 1 X 2 ; wherein X 1 =N and X 2 =A; X 1 =N and X 2 =T; X 1 =S and X 2 =G; X 1 =H and X 2 =G; X 1 =D and X 2 =G; or X 1 =H and X 2 =A. The invention is also concerned with bispecific antibodies that have a heavy chain as defined herein above. The invention is also concerned with methods of production of the antibody, cells producing the antibody and with (medical) uses of the antibody.
1. A method of treating cancer in a subject comprising administering to the subject in need thereof a bispecific antibody which comprises a first heavy chain variable region and light chain variable region combination (VH/VL) that binds human CD3 and a second VH/VL combination that binds a tumor-antigen,
wherein the heavy chain variable region of said first VH/VL combination comprises the complementarity regions, HCDR1, HCDR2 and HCDR3, of the VH set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 58 or SEQ ID NO: 59; and
wherein the light chain variable region of the first VH/VL combination comprises the complementarity regions, LCDR1, LCDR2 and LCDR 3, of the VL set forth in SEQ ID NO: 16.
2. The method of claim 1 , wherein said light chain variable region of said first VH/VL combination, said second VH/VL combination, or both said first and second VH/VL combination comprises a common light chain variable region.
3. The method of claim 2 , wherein said common light chain variable region comprises an O12/IgVκ1-39 light chain variable region.
4. The method of claim 3 , wherein said common light chain variable region is a germline O12/IgVκ1-39*01 variable region.
5. The method of claim 4 , wherein said common light chain variable region comprises the kappa light chain IgVκ1-39*01/IGJκ1*01 or IgVκ1-39*01/IGJκ5*01.
6. The method of claim 5 , wherein said common light chain variable region comprises the germline kappa light chain IgVκ1-39*01/IGJκ1*01 or IgVκ1-39*01/IGJκ5*01.
7. The method of claim 1 , wherein said light chain variable region of said first VH/VL combination comprises the amino acid sequence:
(SEQ ID NO: 16)
DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP
GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP
EDFAT YYCQQ SYSTP PTFGQ GTKVE IK
or
(SEQ ID NO: 17)
DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP
GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP
EDFAT YYCQQ SYSTP PITFG QGTRL EIK.
8. The method of claim 1 , wherein said second VH/VL combination that binds a tumor-antigen binds CLEC12A.
9. The method of claim 1 , wherein said bispecific antibody comprises a human constant region and human variable domains.
10. The method of claim 1 , wherein said bispecific antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains.
11. The method of claim 10 , wherein said compatible heterodimerization domains are compatible immunoglobulin heavy chain CH3 heterodimerization domains.
12. The method of claim 1 , wherein said bispecific antibody is an IgG antibody with a mutant CH2 and/or lower hinge domain such that interaction of said bispecific IgG antibody to a Fc-gamma receptor is reduced.
13. The method of claim 12 , wherein said mutant CH2 and/or lower hinge domain comprises an amino acid substitution at position 235 and/or 236 (Kabat numbering), preferably an L235G and/or G236R substitution.
14. A method of treating cancer in a subject comprising administering to the subject in need thereof a bispecific antibody which comprises a first heavy chain variable region and light chain variable region combination (VH/VL) that binds human CD3 and a second VH/VL combination that binds a tumor-antigen, wherein said first VH/VL combination comprises:
(a) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence GFTFSSYG (SEQ ID NO: 10), a HCDR2 comprising the amino acid sequence IWYNARKQ (SEQ ID NO: 11), and a HCDR3 comprising the amino acid sequence GTGYNWFDP (SEQ ID NO: 12); and
(b) an O12/IgVκ1-39 light chain variable region comprising an LCDR1 comprising the amino acid sequence QSISSY (SEQ ID NO: 18), an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence QQSYSTP (SEQ ID NO: 19).
15. The method of claim 1 , wherein the heavy chain variable region of said first VH/VL comprises an amino acid sequence selected from SEQ ID NOs: 1, 2, 4, 5, 6, 49-51, 53-55 and 57-59.
16. A method of treating cancer in a subject comprising administering to the subject in need thereof a bispecific antibody which comprises a first heavy chain variable region and light chain variable region combination (VH/VL) that binds human CD3 and a second VH/VL combination that binds a tumor-antigen, wherein the heavy chain variable region of said first VH/VL comprises the amino acid sequence set forth in SEQ ID NO: 1, and wherein
(i) the amino acid at position 50 may be substituted with an amino acid selected from Q, S, Y or L;
(ii) the amino acid at position 59 may be substituted with an amino acid selected from L, I, V, F, R, A, N, E, H, S or T;
(iii) the amino acid at position 61 may be substituted with an amino acid selected from N, I, H, Q, L, R, Y, E, S, T, D, K or V; and/or
(iv) the amino acid at position 105 may be substituted with an amino acid selected from M or Y.
17. The method of claim 1 , wherein the heavy chain variable region of said first VH/VL comprises the amino acid sequence set forth in SEQ ID NO: 1.
18. The method of claim 1 , wherein the light chain variable region of said first VH/VL comprises the amino acid sequence set forth in SEQ ID NO: 16.