Anti-PD1 antibodies and their use as therapeutics and diagnostics
Inventors
Li, Kang • Zhang, Tong • Song, Jing • Xu, Lanlan • Liu, Qi • Peng, Hao
Assignees
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Publication Number
US-11186637-B2
Publication Date
2021-11-30
Expiration Date
Abstract
Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) and inhibit PD1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD1-mediated functions.
Core Innovation
The invention is directed to an antibody or antigen-binding fragment thereof that specifically binds to human PD-1 (PDCD-1, CD279). The antibody comprises defined heavy chain variable region complementary determining region (CDR) 1, CDR2, and CDR3 sequences and defined light chain variable region CDR1, CDR2, and CDR3 sequences. The content further describes humanized anti-PD-1 monoclonal antibody families, including hu317 and hu326 variants, that antagonize PD-1/PD-L1/PD-L2 signaling.
The document describes CDR-defined binding domains and links binding to PD-1 epitope residue targeting. It reports critical PD-1 epitope residues targeted by specific antibodies, including K45/193 for hu317-4B5 and hu317-4B6 and 193/L95/P97 for hu326-3B1 and hu326-4A3, as well as additional residue mapping such as I93, L95, P97, I101, and E103.
The invention also describes antibody engineering to modulate Fc effector functions using IgG4 constant domains. It reports IgG4 engineered constant domains, including IgG4mt10 and a specific IgG4 heavy-chain constant domain sequence as SEQ ID NO: 88, to reduce FcγR/C1q binding, thereby lowering ADCC and CDC and improving stability under acidic and high-temperature conditions. The document further associates the antibodies with therapeutic/diagnostic treatment of cancer and viral infections and includes in vivo xenograft findings using human PBMCs showing tumor regression with an IgG4mt2-treated antibody.
Claims Coverage
The independent claims define antibodies or antigen-binding fragments that specifically bind human PD-1 through specified heavy-chain and light-chain variable region CDRs based on SEQ ID NO: 31–36. Across the independent claims, there are two main CDR pattern variations controlling the heavy-chain and light-chain residue ranges, with additional refinements narrowing the antibody to particular full variable region sequences and to IgG4 heavy-chain constant domains, including SEQ ID NO: 88.
Human PD-1 binding via specified heavy- and light-chain CDRs
An antibody or antigen-binding fragment that specifically binds human PD-1, comprising a heavy chain variable region with a heavy chain CDR1 comprising amino acid residues 6-10 of SEQ ID NO: 31, a heavy chain CDR2 comprising the sequence of SEQ ID NO: 32, and a heavy chain CDR3 comprising amino acid residues 3-12 of SEQ ID NO: 33, and comprising a light chain variable region with a light chain CDR1 comprising the sequence of SEQ ID NO: 34, a light chain CDR2 comprising the sequence of SEQ ID NO: 35, and a light chain CDR3 comprising the sequence of SEQ ID NO: 36.
Human PD-1 binding via alternative specified heavy- and light-chain CDR residue ranges
An antibody or antigen-binding fragment that specifically binds human PD-1, comprising a heavy chain variable region with a heavy chain CDR1 comprising amino acid residues 1-8 of SEQ ID NO: 31, a heavy chain CDR2 comprising amino acid residues 2-8 of SEQ ID NO: 32, and a heavy chain CDR3 comprising the sequence of SEQ ID NO: 33, and comprising a light chain variable region with a light chain CDR1 comprising amino acid residues 4-9 of SEQ ID NO: 34, a light chain CDR2 comprising amino acid residues 1-3 of SEQ ID NO: 35, and a light chain CDR3 comprising the sequence of SEQ ID NO: 36.
Overall, the claim set covers human PD-1-specific antibodies defined by detailed heavy-chain and light-chain CDR sequence and residue-range specifications based on SEQ ID NO: 31–36, with refinements that further narrow variable-region definitions and constant-domain format to IgG1 or IgG4 and, in narrower dependents, to an IgG4 heavy-chain constant domain comprising SEQ ID NO: 88.
Stated Advantages
Reduces FcγR/C1q binding, lowering ADCC and CDC.
Improves stability under acidic and high-temperature conditions.
Documented Applications
Therapeutic and diagnostic treatment of cancer.
Therapeutic and diagnostic treatment of viral infections.
In vivo xenograft treatment showing tumor regression using human PBMCs with an IgG4mt2-treated antibody.
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