Method for making multispecific antibodies having heteromultimeric and common components
First Claim
1. A method of preparing a heteromultimeric multispecific antibody comprising the steps of:
- (i) culturing a host cell comprising recombinant nucleic acids which encode a first heavy chain polypeptide, a second heavy chain polypeptide, and a common light chain polypeptide, such that the polypeptides are expressed and form a heteromultimeric multispecific antibody,wherein the first heavy chain polypeptide and the second heavy chain polypeptide each comprise a heavy chain constant domain and a heavy chain variable domain, wherein said first heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a first antigen, and wherein said second heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a different antigen, wherein the common light chain is the only light chain expressed in the host cell, and wherein said first heavy chain polypeptide and said second heavy chain polypeptide multimerize to form a heteromultimeric multispecific antibody; and
(ii) recovering the multispecific antibody from the host cell culture.
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Abstract
The invention relates to a method of preparing heteromultimeric polypeptides such as bispecific antibodies, bispecific immunoadhesins and antibody-immunoadhesin chimeras. The invention also relates to the heteromultimers prepared using the method. Generally, the method provides a multispecific antibody having a common light chain associated with each heteromeric polypeptide having an antibody binding domain. Additionally the method further involves introducing into the multispecific antibody a specific and complementary interaction at the interface of a first polypeptide and the interface of a second polypeptide, so as to promote heteromultimer formation and hinder homomultimer formation; and/or a free thiol-containing residue at the interface of a first polypeptide and a corresponding free thiol-containing residue in the interface of a second polypeptide, such that a non-naturally occurring disulfide bond is formed between the first and second polypeptide. The method allows for the enhanced formation of the desired heteromultimer relative to undesired heteromultimers and homomultimers.
33 Citations
16 Claims
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1. A method of preparing a heteromultimeric multispecific antibody comprising the steps of:
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(i) culturing a host cell comprising recombinant nucleic acids which encode a first heavy chain polypeptide, a second heavy chain polypeptide, and a common light chain polypeptide, such that the polypeptides are expressed and form a heteromultimeric multispecific antibody, wherein the first heavy chain polypeptide and the second heavy chain polypeptide each comprise a heavy chain constant domain and a heavy chain variable domain, wherein said first heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a first antigen, and wherein said second heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a different antigen, wherein the common light chain is the only light chain expressed in the host cell, and wherein said first heavy chain polypeptide and said second heavy chain polypeptide multimerize to form a heteromultimeric multispecific antibody; and (ii) recovering the multispecific antibody from the host cell culture. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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- 15. An isolated host cell comprising recombinant nucleic acid encoding a heteromultimeric multispecific antibody comprising a first heavy chain polypeptide, a second heavy chain polypeptide, and a common light chain polypeptide, wherein each heavy chain polypeptide comprises a heavy chain constant domain and a heavy chain variable domain, wherein said first heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a first antigen, and wherein said second heavy chain polypeptide and said common light chain polypeptide form a binding domain that binds a different antigen, wherein the common light chain is the only light chain expressed in the host cell, and wherein said first heavy chain polypeptide and said second heavy chain polypeptide multimerize to form a heteromultimeric multispecific antibody.
Specification