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Publication Number
US-11851460-B2
Publication Date
2023-12-26
Expiration Date
Abstract
Provided herein are antibody molecules that bind specifically to Programmed cell death 1 (PD1) and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.
Core Innovation
The disclosed invention provides anti-PD1 antibody molecules, including antigen-binding portions, defined by specific heavy chain variable region (VH) and light chain variable region (VL) sequences. The VH and VL sequences are specified by particular HCDR1, HCDR2, and HCDR3 amino acid sequence variants and particular LCDR1, LCDR2, and LCDR3 amino acid sequence variants, with enumerated sequence variants identified by SEQ ID numbers.
A central aspect is engineering onto preferred human germline V-gene frameworks using CDR grafting and germlining. The disclosure covers nucleic acid molecules encoding the anti-PD1 antibody or antigen-binding portions, corresponding vectors, host cells, immunoconjugates, and pharmaceutical compositions.
The antibodies specifically bind human PD1 and, optionally, cynomolgus monkey PD1. The disclosure emphasizes improved binding performance toward both PD1 orthologs, together with high expression and stability, and reports reduced off-target binding versus the prior MAb005 humanized antibody.
Claims Coverage
The relevant independent claim is directed to a nucleic acid molecule encoding specified VH and VL variable-region amino acid sequences of an anti-PD1 antibody or antigen-binding portion, with the CDRs constrained to particular sequence variants. The claim coverage centers on one inventive feature set, with dependent coverage extending the variable-region scaffold context, antibody formats, and selected immunoglobulin constant-region options.
Nucleic acid encoding defined anti-PD1 VH/VL CDR variants
A nucleic acid molecule encoding the heavy chain variable (VH) region amino acid sequence and the light chain variable (VL) region amino acid sequence of an anti-PD1 antibody or an antigen-binding portion thereof, wherein the VH region comprises specified HCDR1/HCDR2/HCDR3 sequence variants and the VL region comprises specified LCDR1/LCDR2/LCDR3 sequence variants.
Human framework scaffold with CDR insertion
The VH and/or VL regions comprise a human variable region framework scaffold amino acid sequence into which the CDRs have been inserted.
Antibody formats from Fab through bis-scFv
The antibody or antigen-binding portion is selected from Fab, Fab′, F(ab′)2, Fv, scFv, maxibody, minibody, diabody, triabody, tetrabody, or bis-scFv.
Selected immunoglobulin constant-region variants including IgG1 L234A/L235A/G237A and IgG4 S228P
The immunoglobulin constant region is one of specified human Ig variants, including wild-type or substitution-containing IgG4 constant region with S228P, wild-type or substitution-containing IgG1 constant region with L234A, L235A and G237A, and a wild-type human IgG2 constant region.
Constant region restricted to SEQ ID NOS:13-19
The immunoglobulin constant region comprises any one of SEQ ID NOS:13-19.
Overall, the claim set centers on nucleic acids encoding anti-PD1 variable regions defined by enumerated HCDR and LCDR sequences, with dependent claim coverage that further limits the variable-region scaffold context, enumerates allowed antibody formats, and restricts the constant region to specified Ig variants and sequence IDs.
Stated Advantages
Improved human and cyno PD1 potency/affinity for library-derived and designer IgGs, reported with normalized human/cyno KD differential for lead clones.
High expression and stability.
Improved Fab thermal stability as determined by DSC.
Reduced oxidative susceptibility relative to the humanized Mab005.
Markedly reduced off-target binding versus the prior MAb005 humanized antibody.
Ablated binding to KDR/VEGFR2, FZD5, ULBP2, and EPHB6 versus MAb005.
Engineered lead antibodies show ablated off-target reactivity compared with Mab005, including ablated receptor activation in a VEGFR2 activation reporter for lead clones.
Reduced T-cell epitope risk via in silico immunogenicity/deimmunization analysis.
Documented Applications
Binding and characterization of anti-PD1 antibodies, including direct binding ELISA, epitope competition, SPR KD determination, and flow cytometry binding to PD1 on human and cynomolgus cells.
Functional PD1/PD-L1 antagonism in a cell-based blockade assay.
Off-target liability assessment using a human receptor array and orthogonal assays, including a VEGFR2 activation reporter assay to evaluate receptor activation for lead clones.
Deimmunization-related evaluation using iTope and TCED with predicted germline MHC class II epitope content changes associated with sequence changes in CDRs.
Cancer treatment using the anti-PD1 antibody molecules and related formats such as antigen-binding portions and immunoconjugates.
Infectious disease treatment, including HIV.
Use in immunoconjugates and pharmaceutical compositions for the above medical uses.
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