PD-1-binding molecules and methods of use thereof
Inventors
Shah, Kalpana • Smith, Douglas H. • Motte-Mohs, Ross La • Johnson, Leslie S. • Moore, Paul A. • Bonvini, Ezio • Koenig, Scott
Assignees
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Publication Number
US-11623959-B2
Publication Date
2023-04-11
Expiration Date
Abstract
The present invention is directed to selected anti-PD-1 antibodies capable of binding to both cynomolgus monkey PD-1 and to human PD-1: PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mAb 5, PD-1 mAb 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14, or PD-1 mAb 15, and to humanized and chimeric versions of such antibodies. The invention additionally pertains to PD-1-binding molecules that comprise PD-1 binding fragments of such anti-PD-1 antibodies, immunocongugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., that comprise (i) such PD-1-binding fragments, and (ii) a domain capable of binding an epitope of a molecule involved in regulating an immune check point present on the surface of an immune cells. The present invention also pertains to methods of using molecules that bind PD-1 for stimulating immune responses, as well as methods of detecting PD-1.
Core Innovation
The invention relates to a bispecific binding molecule capable of binding to PD-1 and LAG-3. The bispecific molecule comprises a PD-1-binding domain and a LAG-3 binding domain, each including a Variable Heavy Chain Domain and a Variable Light Chain Domain, with the PD-1-binding domain defined by CDR H1, CDR H2, CDR H3, and CDR L1, CDR L2, CDR L3 corresponding to hPD-1 mAb 7(1.2).
The LAG-3 binding domain likewise comprises a Variable Heavy Chain Domain and a Variable Light Chain Domain, including CDR H1, CDR H2, CDR H3, and CDR L1, CDR L2, CDR L3, with the LAG-3 binding CDRs defined relative to hLAG-3 mAb 6 and sequence-defined embodiments. The disclosed subject matter further includes bispecific formats such as a diabody configuration as a covalently bonded complex and a bispecific antibody, together with sequence-defined diabody embodiments characterized by SEQ ID NO:290 and SEQ ID NO:291.
Additional refinements describe engineered Fc regions to modulate FcγR binding and extend serum half-life, including IgG1, IgG2, IgG3, or IgG4 isotypes and, for IgG4, an IgG4 hinge domain with a stabilizing mutation. The Fc engineering includes specific Fc amino acid substitutions, optional absence of C-terminal lysine, altered FcγR binding to reduce or abolish ADCC or to modify interactions with CD64, CD32A/B, and CD16a/b, and knob-into-hole CH2/CH3 heterodimerization engineering to support desired Fc functional properties and heterodimerization.
Claims Coverage
The independent claims include two inventive scopes: a PD-1/LAG-3 bispecific binding molecule defined by specified PD-1 and LAG-3 CDR sets, and a PD-1/LAG-3 bispecific diabody defined as a covalently bonded complex with specified polypeptide chain assignments. The inventive coverage also includes optional or dependent structures and Fc-region engineering features in the claim set for the first independent claim.
PD-1 and LAG-3 dual binding with specified CDRs
A bispecific binding molecule capable of binding to PD-1 and LAG-3, comprising a PD-1-binding domain with a Variable Heavy Chain Domain and a Variable Light Chain Domain, wherein the Variable Heavy Chain Domain CDR1, CDR2, and CDR3 are the heavy-chain CDRs of hPD-1 mAb 7(1.2), and the Variable Light Chain Domain CDR1, CDR2, and CDR3 are the light-chain CDRs of hPD-1 mAb 7(1.2), and a LAG-3 binding domain comprising a Variable Heavy Chain Domain and a Variable Light Chain Domain having respective CDRs.
Covalently bonded four-chain bispecific diabody with defined chain identities
A bispecific diabody capable of binding to PD-1 and LAG-3, wherein the bispecific diabody is a covalently bonded complex that comprises four polypeptide chains, wherein two of the polypeptide chains comprise SEQ ID NO:290 and two of the polypeptide chains comprise SEQ ID NO:291.
Overall, the claims cover a PD-1/LAG-3 bispecific binding molecule defined by specified PD-1 CDRs and defined LAG-3 CDRs, with further structural embodiments that include diabody and covalently bonded formats. The diabody-independent scope additionally fixes the covalently bonded four-chain structure via explicit assignments of SEQ ID NO:290 and SEQ ID NO:291.
Stated Advantages
Attenuates PD-1/LAG-3 inhibitory activity as described in the partial content.
Reduces or abolishes ADCC by altering FcγR binding as described in the partial content.
Modifies receptor interactions (CD64, CD32A/B, CD16a/b) as described in the partial content.
Supports desired Fc heterodimerization and functional properties using knob-into-hole engineering as described in the partial content.
Extends serum half-life as described in the partial content.
Documented Applications
Therapeutic/pharmaceutical use context is mentioned broadly in the partial content.
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