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JP-7857104-B2 - CD3 binding molecule

JP7857104B2JP 7857104 B2JP7857104 B2JP 7857104B2JP-7857104-B2

Inventors

  • ピーテル・フォッコ・ファン・ロー

Assignees

  • メルス・ベー・フェー

Dates

Publication Date
20260512
Application Date
20200327
Priority Date
20190329

Claims (18)

  1. An antigen-binding protein that binds to human CD3, comprising an antibody-variable domain including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the following amino acid sequence: CDR1: SFGIS , CDR2: GFIPVLGTANYAQKFQG , CDR3: RGNWNPFDP, Or amino acid sequence: CDR1: SKTFTIS, CDR2:GIIPLFGTITYAQKFQG, CDR3: RGNWNPFDP, Alternatively, CDR1: SRTFTIS, CDR2: S IIPIFGTITYAQKFQG, CDR3: RGNWNPFDP Includes CDR1, CDR2 and CDR3, and, The aforementioned light chain variable region has the following amino acid sequence: CDR1: QSISSY, CDR2: AAS, CDR3:QQSYSTP Antigen-binding proteins including CDR1, CDR2, and CDR3.
  2. An antigen-binding protein that binds to human CD3, comprising an antibody-variable domain including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the following amino acid sequence: CDR1: SKTLTIS, CDR2: GIIPIFGSITYAQKFQD, CDR3: RGNWNPFDP Includes CDR1, CDR2 and CDR3, and The aforementioned light chain variable region has the following amino acid sequence: CDR1: QSISSY, CDR2: AAS, CDR3:QQSYSTP Antigen-binding proteins including CDR1, CDR2, and CDR3.
  3. The antibody comprises a variable domain including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is an amino acid sequence EVQLVQSGAEVKKPGSSSVKVSCKASGGGTFRSFGISWVRQAPGQGLEWMGGGFIPVLGTANYAQKFQGRVTIIADKSTNTAYMELSSLRSEDTAVYYCARRGNWNPFDPWGQGTLVTVSS, or QVQLVQSGAEVKKPGSSSVKVSSCKASGDAFKSKTFTISWVRQAPGQGLEWLGGIIPLFGTITYAQKFQGRVTITITADKSTNTATAFMELSSLRSEDTAMYYYCTRRGNWNPFDDPWGQGTLVTVSS, or EVQLVQSGSELKKPGGSSVKVSSCKASGVTFNSRTFTISWVRQAPGQGLEWLGSIIPIFGTITYAQKFQGRVTITITADKSTSTAAFMELTSLRSEDTAIYYYCTRRGNWNPFDDPWGQGTLVTVSS, or QVQLVQSGAEVKKPGSSSVKVSCKASGVTFKSKTLTISWVRQAPGQGLEWLGGIIPIFGSITYAQKFQDRVSITADKSTNTAYLELNSLRSEDTAIYYCARRGNWNPFDPWGQGTLVTVSS includes, At one or more positions other than the CDR, there are insertions, deletions, substitutions, additions, or combinations thereof of 0 to 10 amino acids, and The light chain variable region is an amino acid sequence DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP EDFAT YYCQQ SYSTP PTFGQ GTKVE IK, or DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP EDFAT YYCQQ SYSTP PITFG QGTRL EIK included, The antigen-binding protein according to claim 1 or 2 , having 0 to 5 amino acid insertions , deletions, substitutions, additions, or combinations thereof at one or more positions other than the CDR.
  4. The heavy chain variable region is an amino acid sequence EVQLVQSGAEVKKPGSSSVKVSCKASGGGTFRSFGISWVRQAPGQGLEWMGGGFIPVLGTTANYAQKFQGRVTIIADKSTNTAYMELSSLRRSEDTAVYYCARRGNWNPFDPWGQGTLVTVSS, or QVQLVQSGAEVKKPGSSVKVSSCKASGDAFKSKTFTISWVRQAPGQGLEWLGGIIPLFGTITYAQKFQGRVTITITADKSTNTAFFMELSSLRSEDTAMYYYCTRRGNWNPFDPWGQGTLVTVSS, or EVQLVQSGSELKKPGSSSVKVSCKASGVTFNSRTFTISWVRQAPGQGLEWLGSIIPIFGTITYAQKFQGRVTITATADKSTSTAFMELTSLRSEDTAIYYCTRRGNWNPFDPWGQGTLVTVSS, or QVQLVQSGAEVKKPGSSSVKVSCKASGVTFKSKTLTISWVRQAPGQGLEWLGGIIPIFGSITYAQKFQDRVSITADKSTNTAYLELNSLRSEDTAIYYCARRGNWNPFDPWGQGTLVTVSS includes, At one or more positions other than the CDR, there are insertions, deletions, substitutions, additions, or combinations thereof of 0 to 5 amino acids, and The light chain variable region is an amino acid sequence DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP EDFAT YYCQQ SYSTP PTFGQ GTKVE IK, or DIQMT QSPSS LSASV GDRVT ITCRA SQSIS SYLNW YQQKP GKAPK LLIYA ASSLQ SGVPS RFSGS GSGTD FTLTI SSLQP EDFAT YYCQQ SYSTP PITFG QGTRL Including EIK, The antigen-binding protein according to claim 1 or 2, having 0 to 5 amino acid insertions, deletions, substitutions, additions, or combinations thereof at one or more positions other than the CDR.
  5. An antigen-binding protein according to any one of claims 1 to 4 , which is an antibody .
  6. An antigen-binding protein according to any one of claims 1 to 4, which is a bispecific antibody.
  7. The antigen-binding protein according to claim 6 , wherein the bispecific antibody comprises the H/L chain combination described in any one of claims 1 to 4 and the H/L chain combination that binds to a tumor antigen .
  8. The antigen-binding protein according to claim 7, wherein the H/L chain combination that binds to the tumor antigen binds to human BCMA, CD19, CD20, CD30, CD33, CD38, CD44, CD123, CD138, CEA, CLEC12A, CS-1, EGFR, EGFRvIII, EPCAM, DLL3, LGR5, MSLN, FOLR1, FOLR3, HER2, HM1.24, MCSP, PD- L1 , PSMA protein , or a variant thereof.
  9. The antigen-binding protein according to any one of claims 5 to 8 , wherein the antibody is human or a humanized antibody.
  10. The antigen-binding protein according to any one of claims 6 to 9 , wherein the bispecific antibody comprises two different immunoglobulin heavy chains having compatible heterodimerization domains.
  11. The antigen-binding protein according to claim 10 , wherein the compatible heterodimer domain is a compatible immunoglobulin heavy chain CH3 heterodimer domain.
  12. The antigen-binding protein according to any one of claims 6 to 11 , wherein the bispecific antibody is an IgG antibody and has a mutated CH2 and/or lower hinge domain such that the interaction between the bispecific IgG antibody and the Fc gamma receptor is reduced.
  13. The antigen-binding protein according to claim 12 , wherein the mutated CH2 and/or lower hinge domain includes amino acid substitutions at positions 235 and/or 236 (according to EU numbering).
  14. The antigen-binding protein according to claim 13, wherein the mutated CH2 and/or lower hinge domain comprises an L235G substitution and/or a G236R substitution.
  15. The antigen-binding protein according to any one of claims 6 to 14 , wherein the bispecific antibody comprises a common light chain.
  16. An antigen-binding protein according to any one of claims 1 to 15 , for use in the treatment of a subject requiring such treatment.
  17. The antigen- binding protein according to claim 16 , wherein the subject has cancer or is being treated for cancer.
  18. The antigen-binding protein according to claim 16 or 17 , wherein the treatment comprises local administration and/or local release of the antigen -binding protein according to claim 1 or 2.

Description

This invention relates to the field of antibodies, particularly to therapeutic antibodies. Antibodies can be used to treat humans. More specifically, this invention relates to antibodies for the treatment of tumors, preferably bispecific or multispecific antibodies. Monoclonal antibodies that bind to human CD3 were among the first antibodies developed for therapeutic use in humans. Monoclonal CD3-binding antibodies are typically used, for example, in cases of transplant rejection, due to their immunosuppressive properties. Antibodies that are bispecific to CD3 on T cells and to surface target antigens on cancer cells can link any type of T cell to cancer cells, regardless of T cell receptor specificity, co-stimulation, or peptide antigen presentation. Such bispecific T cell-engaging antibodies hold great promise in the treatment of various cancers and tumor growth. The object of the present invention is to provide a novel antibody with improved properties, possessing CD3 binding characteristics, not necessarily perfect but essentially, with higher cytotoxicity and relatively low affinity, suitable for immuno-oncological applications for the engagement of T cells and effector cells; and conversely, a novel antibody with lower cytotoxicity and relatively high affinity CD3 binding, suitable for autoimmune applications for the downregulation of T cells and effector cells. A further object of the present invention is to provide a T cell-engaging CD3-binding protein and antibody possessing the above properties, which bind to at least one further membrane-bound molecule. The present invention provides an antigen-binding protein, preferably an antibody, that binds to human CD3, comprising an antibody-variable domain including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the following amino acid sequence: CDR1: SFGIS CDR2: GFIPVLGTANYAQKFQG CDR3: RGNWNPFDP, or amino acid sequence: CDR1:SX 1 TFTIS, CDR2: GIIPX 2 FGTITYAQKFQG, CDR3: RGNWNPFDP, (In the array, X 1 = K or R, Includes CDR1, CDR2, and CDR3 (where X² = L or I). In a preferred embodiment, X1 = K and X2 = L. In a preferred embodiment, X1 = R and X2 = I. In a preferred embodiment, the present invention provides an antigen-binding protein, preferably an antibody, that binds to human CD3, comprising an antibody-variable domain including a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region has the following amino acid sequence: CDR1: SKTLTIS, CDR2: GIIPIFGSITYAQKFQD, CDR3: RGNWNPFDP, or amino acid sequence: CDR1: GSGIS, CDR2: GFIPFFGSANYAQKFRD, CDR3: RGNWNPX 13 DP (In the array, Includes CDR1, CDR2, and CDR3 containing X 13 (where X = L or F). The present invention further provides an antigen-binding protein, preferably an antibody, that binds to human CD3, comprising an antibody-variable domain including a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region has the amino acid sequence EVQLVQSGAEVKKPGSSSVKVSCKASGGGTFRSFGISWVRQAPGQGLEWMGGGFIPVLGTANYAQKFQGRVTIIADKSTNTAYMELSSLRSEDTAVYYCARRGNWNPFDPWGQGTLVTVSS, QVQLVQSGAEVKKPGSSVKVSCKASGDAFKSKTFTISWVRQAPGQGLEWLGGIIPLFGTI TYAQKFQGRVTITADKSTNTAFMELSSLRSEDTAMYYCTRRGNWNPFDPWGQGTLVTVSS, EVQLVQSGSELKKPGSSVKVSCKASGVTFNSRTFTISWVRQAPGQGLEWLGSIIPIFGTI TYAQKFQGRVTITADKSTSTAFMELTSLRSEDTAIYYCTRRGNWNPFDPWGQGTLVTVSS, QVQLVQSGAEVKKPGSSVKVSCKASGGTFRGSGISWVRQAPGQGLEWVGGFIPFGSAN YAQKFRDRVTITADKSATTAYMELSSLRSEDTAIYYCAKRGNWNPLDPWGQGTLVTVSS, QVQLVQSGAEVKKPGSSVKVSSCKASGVTFKSKTLTISWVRQAPGQGLEWLGGIIPIFGSITYAQKFQDRVSITADKSTNTAYLELNSLRSEDTAIYYCARRGNWNPFDDPWGQGTLVTVSS, or EVQLVQSGAEVKKPGGSSVKVSSCKASGGTFRRGSGISWVRQAPGQGLEWVGGFIPFFGSANYAQKFRDRVTITITADKSATTAYMELSSLRSEDTAIYYCAKRGNWNPFDDPWGQGTLVTVSS, At one or more positions other than the CDR, there are 0 to 10, preferably 0 to 5, amino acid mutations, insertions, deletions, substitutions, additions, or combinations thereof. Further provided is an antigen-binding protein, preferably an antibody, that binds to human CD3, comprising an antibody-variable domain including a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the following amino acid sequence: CDR1:RX 3 WIG, CDR2: IIYPGDSDTRYSPSFQG, CDR3:X 4 IRYFX 5 WSEDYHYYX 6 DV (In the array, X 3 = F or Y, X 4 = H or N, X 5 = D or V, Includes CDR1, CDR2, and CDR3 (where X 6 = L or M). In one embodiment , X3 = F, X4 = H, X5 = D, and X6 = L. In another embodiment, X3 = Y, X4 = N, X5 = V, and X6 = M. The present invention further provides an antigen-binding protein, preferably an antibody, that binds to human CD3, comprising an antibody-variable domain including a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region is an amino acid sequence EVQLVQSGAEVKKPGESLKISCKGSGYSFTRFWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSTSTAYLQWSSLKASDTGMYYCVRHIRYFDWSEDYHYYLDVWGKGTTVTVSS, or Including EVQLVES