JP2013520984A5 - - Google Patents

Claims (25)

An antibody composition comprising a first recombinant anti-HER2 antibody and a second recombinant anti-HER2 antibody that bind to distinct epitopes of HER2, comprising:
(a) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 53 and 80, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 56 and 82, respectively. Or;
(b) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 53 and 80, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 62 and 86, respectively. Or;
(c) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 53 and 80, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 50 and 78, respectively. Or;
(d) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 56 and 82, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 65 and 88, respectively. Or;
(e) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 56 and 82, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 50 and 78, respectively. Or;
(f) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 59 and 84, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 50 and 78, respectively. Or;
(g) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 62 and 86, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 65 and 88, respectively. Or;
(h) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 62 and 86, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 47 and 76, respectively. Or; or
(i) the first antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 65 and 88, respectively, and the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 50 and 78, respectively. The composition which is mu. An antibody composition comprising a first recombinant anti-HER2 antibody and a second recombinant anti-HER2 antibody that bind to distinct epitopes of HER2, wherein the first antibody is a heavy chain of SEQ ID NOs: 62 and 86, respectively. A composition comprising a chain and light chain CDR3 sequence, and wherein the second antibody comprises the heavy and light chain CDR3 sequences of SEQ ID NOs: 47 and 76, respectively. The antibody composition of claim 2, wherein the first antibody comprises the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 22 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 24, The second antibody comprises the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 2 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 4, and a residue in one of said CDRs is amidolytic A composition that has changed to remove sites. An antibody composition comprising a first recombinant anti-HER2 antibody and a second recombinant anti-HER2 antibody that binds to distinct epitopes of HER2, or a humanized variant of said antibody, said first antibody Comprises the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 22 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 24, and the second antibody is the heavy chain CDR1 in SEQ ID NO: 2 , A CDR2 and CDR3 sequence and a light chain CDR1, CDR2 and CDR3 sequence in SEQ ID NO: 4. The first antibody comprises a heavy chain variable region in the amino acid sequence of SEQ ID NO: 22 and a light chain variable region in the amino acid sequence of SEQ ID NO: 24, and the second antibody in the amino acid sequence of SEQ ID NO: 2 5. The antibody composition of claim 4, comprising a heavy chain variable region and a light chain variable region in the amino acid sequence of SEQ ID NO: 4. An antibody composition comprising a first recombinant anti-HER2 antibody and a second recombinant anti-HER2 antibody that bind to distinct epitopes of HER2, comprising:
(a) the same first antibody binds to an anti-HER2 antibody comprising the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 22 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 24 Binds to an epitope and competes for binding with an anti-HER2 antibody comprising the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 22 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 24; And,
(b) The second antibody is the same as the anti-HER2 antibody comprising the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 2 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 4 binds Binds to an epitope and competes for binding with an anti-HER2 antibody comprising heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 2 and light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 4, Composition. Binds to the same epitope to which an anti-HER2 antibody comprising the heavy chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 14 and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 16 binds; and SEQ ID NO: 14 A third recombinant anti-HER2 antibody that competes for binding with an anti-HER2 antibody comprising the heavy chain CDR1, CDR2 and CDR3 sequences in and the light chain CDR1, CDR2 and CDR3 sequences in SEQ ID NO: 16. The antibody composition according to any one of 1 to 6. 8. The antibody composition of any of claims 1-7, wherein at least one anti-HER2 antibody in the composition is humanized. 9. The antibody composition of any of claims 1-8, wherein at least one anti-HER2 antibody in the composition is of the IgG isotype. The antibody composition according to any one of claims 1 to 9, wherein at least one anti-HER2 antibody in the composition is an immune complex comprising an anticancer agent. A bispecific binding molecule having the binding specificity of the first and second antibodies according to any one of claims 1 to 6. 12. The bispecific binding molecule of claim 11 that binds to the same HER2 epitope to which the following antibody binds and competes for binding with the following antibody:
(a) an anti-HER2 antibody comprising the amino acid sequence of SEQ ID NOS: 22 and 24; and
(b) an anti-HER2 antibody comprising the amino acid sequences of SEQ ID NOs: 2 and 4. A nucleic acid molecule comprising a nucleotide sequence encoding a heavy chain variable region, a light chain variable region or both of a recombinant anti-HER2 antibody as defined in any of claims 1-9. An expression vector comprising the nucleic acid molecule of claim 13. A host cell comprising a nucleotide sequence encoding the heavy chain variable region of a recombinant anti-HER2 antibody as defined in any of claims 1 to 9 and a nucleotide sequence encoding the light chain variable region of the recombinant anti-HER2 antibody A host cell capable of expressing the recombinant anti-HER2 antibody. A method for producing a recombinant anti-HER2 antibody, comprising providing the host cell of claim 15, culturing said host cell under conditions suitable for expression of said antibody, and the resulting antibody A method comprising isolating. A method for producing an antibody composition comprising first and second recombinant anti-HER2 antibodies, comprising the following steps:
Providing a first host cell and a second host cell, each of said first and second host cells comprising a recombinant anti-HER2 antibody as defined in any of claims 1-6. A process that is capable of being expressed;
Culturing the first and second host cells under conditions suitable for expression of the first and second recombinant antibodies; and
Separating the resulting first and second recombinant antibodies. 18. The method of claim 17, wherein the first and second host cells are cultured in a single bioreactor. A pharmaceutical composition comprising the antibody composition of any of claims 1 to 10, or the bispecific binding molecule of claim 11 or 12, and a pharmaceutically acceptable diluent, carrier or excipient. A pharmaceutical composition comprising the antibody composition of any of claims 1-10 or the bispecific binding molecule of claim 11 or 12 for treating cancer in humans. 13. A pharmaceutical composition comprising the antibody composition of any of claims 1-10 or the bispecific binding molecule of claim 11 or 12 for treating a patient having a disease characterized by overexpression of HER2. 11. The antibody composition of any of claims 1-10 or claim 11 or 12 for reducing heterodimer formation between HER2 and other ErbB family receptors in cells that overexpress HER2. A pharmaceutical composition comprising a bispecific binding molecule of A pharmaceutical composition comprising the antibody composition of any of claims 1-10 or the bispecific binding molecule of claim 11 or 12 for inducing internalization of HER2 on the surface of a cell overexpressing HER2. object. 13. The antibody composition of any of claims 1-10 or of claims 11 or 12, for inhibiting the growth of tumor cells that are resistant or partially resistant to treatment with an anti-HER2 antibody. A pharmaceutical composition comprising a bispecific binding molecule. 25. The pharmaceutical composition of claim 24, wherein the tumor cells have been previously treated with trastuzumab.