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US 2019/0292268 A1Published application
Methods for Producing Fabs and IgG Bispecific Antibodies
AssigneesEli Lilly and Company, The University of North Carolina at Chapel Hill
InventorsStephen John Demarest, Karen Jean Froning, Brian Arthur Kuhlman, Andrew Philip Leaver-Fay
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Abstract
The present invention provides methods for producing Fabs and IgG bi-specific antibodies comprising expressing nucleic acids encoding designed residues in CH1/CL interface, Fabs and IgG bi-specific antibodies produced according to said processes as well as nucleic acids, vectors and host cells encoding the same.
Claims41
A method for producing a first and second fragment, antigen binding (Fab) comprising:
- (1) co-expressing in a host cell:
- (a) a first nucleic acid sequence encoding both a first heavy chain variable domain (VH) and a first human IgG heavy chain constant CH1 (CH1) domain, wherein said first human CH1 domain comprises an alanine at residue 145 (according to Kabat Numbering);
- (b) a second nucleic acid sequence encoding both a first light chain variable domain (VL) and a first human light chain kappa constant (Ck) domain, wherein said first human Ck domain comprises an arginine at residue 131 (according to Kabat Numbering);
- (c) a third nucleic acid encoding both a second VH domain and a second human CH1 domain, wherein said second human CH1 domain has the wide type human IgG CH1 sequence;
- and
- (d) a fourth nucleic acid encoding both a second VL domain and a second human Ck domain, wherein said second human Ck domain has the wide type human Ck sequence, wherein each of said first VH and VL domains comprise three complementarity determining regions (CDRs) which direct binding to a first antigen and further wherein each of said second VH and VL domains comprise three CDRs which direct binding to a second antigen that differs from said first antigen;
- (2) cultivating said host cell under conditions such that said first and second VH and human CH1 domains and said first and second VL and human Ck domains are produced;
- and
- (3) recovering from said host cell a first and second Fabs wherein said first Fab comprises said first VH and first human CH1 domains and said first VL and first human Ck domains, and said second Fab comprises said second VH and second human CH1 domains and said second VL and second human Ck domains.
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A method for producing a bispecific antibody comprising:
- (1) co-expressing in a host cell:
- (a) a first nucleic acid sequence encoding both a first VH domain and a first human IgG heavy chain constant region, wherein said first human IgG heavy chain constant region comprises a first human CH1 domain comprising an alanine at residue 145 (according to Kabat Numbering);
- (b) a second nucleic acid sequence encoding both a first VL domain and a first human Ck domain, wherein said first human Ck domain comprises an arginine at residue 131 (according to Kabat Numbering);
- (c) a third nucleic acid encoding both a second VH and a second human IgG heavy chain constant region, wherein said second human IgG heavy chain constant region comprises a second human CH1 domain that has the wide type human IgG CH1 sequence;
- and
- (d) a fourth nucleic acid encoding both a second VL and a second human Ck domain, wherein said second human Ck domain has the wide type human Ck sequence, wherein each of said first VH and VL domains comprise three CDRs which direct binding to a first antigen and further wherein each of said second heavy chain and light chain variable domains comprise three CDRs which direct binding to a second antigen that differs from said first antigen;
- (2) cultivating said host cell under conditions such that said first and second VH and human CH1 domains and said first and second VL and human Ck domains are produced;
- and
- (3) recovering from said host cell an IgG bispecific antibody comprising a first and second Fabs wherein said first Fab comprises said first VH and first human CH1 domains and said first VL and first human Ck domains, and said second Fab comprises said second VH and second human CH1 domains and said second VL and second human Ck domains.
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A bispecific antibody comprising:
- (a) a first heavy chain, wherein said first heavy chain comprises a first variable domain (VH) and a first human IgG1 or IgG4 constant region, wherein said first human IgG1 or IgG4 constant region comprises a first CH1 domain comprising an alanine at residue 145 (according to Kabat Numbering);
- (b) a first light chain, wherein said first light chain comprises a first variable domain (TA) and a first human light chain kappa domain (CK), wherein said first human CK domain comprises an arginine at residue 131 (according to Kabat Numbering);
- (c) a second heavy chain, wherein said second heavy chain comprises a second VH domain and a second human IgG1 or IgG4 constant region, wherein said second human IgG1 or IgG4 heavy chain constant region comprises a second CH1 domain that has the wide type human IgG1 or IgG4 CH1 sequence;
- and
- (d) a second light chain, wherein said second light chain comprises a second VL and a second human CK, wherein said second human light chain kappa domain has the wide type human Cκ sequence, wherein each of said first VH and VL domains comprise three CDRs) which direct binding to a first antigen and further wherein each of said second VH and VL domains comprise three CDRs which direct binding to a second antigen that differs from said first antigen.
2 more elements
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-45. (canceled)
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Dependencies are inferred from the claim text.