Heterodimeric antibodies that bind prostate specific membrane antigen (PSMA) and CD3

Inventors

Desjarlais, John R. • Nisthal, Alex • Hedvat, Michael • Dragovich, Matthew Adam

Assignees

Xencor Inc

Abstract

Provided herein are novel antigen binding domains and antibodies (e.g., heterodimeric antibodies) that bind Prostate Specific Membrane Antigen (PSMA). In exemplary embodiments, the anti-PSMA antibodies also bind CD3. Such antibodies that bind PSMA and CD3 are useful, for example in the treatment of PSMA-related cancer.

Core Innovation

The disclosed subject matter relates to anti-PSMA×anti-CD3 bispecific antibodies that include PSMA and CD3 antigen binding domains. The disclosure emphasizes heterodimeric antibody formats in which antigen binding domains are arranged around a scaffold, including formats described as 1+1 Fab-scFv-Fc, mAb-Fv, mAb-scFv, 2+1 Fab2-scFv-Fc, central-Fv, one-armed central-scFv, one-armed scFv-mAb, scFv-mAb, dual scFv, and Trident.

The antigen binding elements are represented using variable regions such as VH and VL and corresponding complementarity determining regions. The disclosure further describes orientation options for scFv arms using relative positioning of VH-scFv linker-VL or VL-scFv linker-VH, together with engineering options for antigen binding and Fc-containing regions, including CDR/framework variants, linker choices, Fc skew/pI/ablation/FcRn engineering, and additional Fc variants.

Representative engineering examples include FcRn variants, including M428L/N434S and Xtend mutation (M428L/N434S), alongside pI engineering. In addition, the disclosure describes DNA/nucleic acids encoding the antibody components and expression formats, together with expression and purification considerations described in the partial content.

Functional characterization is described using PSMA-expressing surrogate cell lines and measuring PSMA binding and cellular activity with assays such as IHC and FACS, including MESF/QuickCal, affinity screening using Octet/BLI, and redirected T-cell cytotoxicity assessments, including RTCC and CD107a degranulation. The disclosure also includes in vivo anti-tumor activity in NSG mice plus tolerability and pharmacokinetics in cynomolgus monkeys, including terminal half-life and clearance.

Claims Coverage

The independent claims in the provided list cover PSMA binding domain compositions defined by specific variable heavy and variable light domain sequence identities and CDR contents. Across the independent-claim family, the core coverage focuses on one specific variable heavy domain (SEQ ID NO: 217) combined with one of three alternative variable light domains (SEQ ID NOs: 252, 257, or 286), yielding multiple composition embodiments.

Based on the provided independent-claim texts, the claim coverage is centered on PSMA binding domain compositions formed from a fixed variable heavy domain sequence (SEQ ID NO: 217) and an alternative variable light domain sequence set (SEQ ID NOs: 252, 257, or 286).

Stated Advantages

Documented Applications