Anti-CD28 x anti-PSMA antibodies
Inventors
Desjarlais, John R. • Moore, Gregory • Hedvat, Michael • Diaz, Juan • Gusti Zeng, Veronica • Dragovich, Matthew Adam • ERHARDT, JOSEPH • McDevitt, Theresa • Moussa, Fouad • Seth, Pankaj • Shen, Fei • ZWOLAK, Adam
Assignees
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Publication Number
US-12365743-B2
Publication Date
2025-07-22
Expiration Date
Abstract
Provided herein are novel anti-CD28× anti-PSMA antibodies and methods of using such antibodies for the treatment of PSMA-associated cancers. Subject anti-CD28× anti-PSMA antibodies are capable of agonistically binding to CD28 costimulatory molecules on T cells and PSMA on tumor cells. Thus, such antibodies selectively enhance anti-tumor activity at tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies (e.g., anti-CD3× anti-PSMA antibodies) for the treatment of prostate cancers.
Core Innovation
The invention relates to heterodimeric antibody formats that combine specified antigen binding domains for Prostate Specific Membrane Antigen (PSMA) and CD28 with engineered Fc and charge properties. The disclosed heterodimeric design includes a first monomer with an scFv covalently attached to the N-terminus of a first Fc domain using a domain linker, and a second monomer with a VH1-CH1-hinge-CH2-CH3 arrangement in which CH2-CH3 forms a second Fc domain.
In these structures, VH1 and VL1 form a first antigen binding domain that binds PSMA, and VH2 and VL2 form a second antigen binding domain that binds CD28. The architectures include a 1+1 Fab-scFv-Fc format, a 2+1 Fab2-scFv-Fc format, and a 1+1 common light chain format, together with related anti-CD28×anti-PSMA configurations such as 2+1 CLC format antibody and other scFv/Fv placements.
The invention further describes pI- and Fc-based variants, including hinge (EU 216–230) and CH2/CH3 pI-lowering substitutions, isotype importation, FcRn half-life variants, Fc heterodimerization skew variants, FcγR ablation variants, and purification variants that reduce Protein A binding. The content also mentions charged scFv linkers, including (GKPGS)4, and pI differences of ≤0.5 for ion-exchange and IEF purification and monitoring of mispaired homodimer species.
Claims Coverage
The provided content identifies one independent claim and describes a heterodimeric antibody with two distinct antigen-binding domains for PSMA and CD28, together with defined monomer architecture and variable domain sequences.
Heterodimeric antibody with PSMA- and CD28-binding antigen binding domains
A heterodimeric antibody comprises a first monomer with an scFv covalently attached to the N-terminus of a first Fc domain using a domain linker and a second monomer having a VH1-CH1-hinge-CH2-CH3 architecture where CH2-CH3 is a second Fc domain, together forming a first antigen binding domain that binds PSMA and a second antigen binding domain that binds CD28.
Light chain architecture and defined variable domain sequences
A light chain comprises a VL1-CL arrangement, and VH1, VH2, VL1, and VL2 are defined by amino acid sequences of SEQ ID NOs 214, 396, 218, and 400, respectively.
The claim coverage centers on a heterodimeric antibody architecture that combines PSMA-binding VH1/VL1 and CD28-binding VH2/VL2 into a two-monomer, Fc-based format with an scFv linked to one Fc domain, an ordered VH1-CH1-hinge-CH2-CH3 second monomer, and specified variable domain sequences.
Stated Advantages
Enhances anti-tumor activity at tumor sites.
Minimizes peripheral toxicity.
Provides trivalent/bi-/multi-specific anti-CD28×anti-PSMA antibody formats depending on placement or orientation of scFv/Fv domains.
Documented Applications
Used for PSMA-associated cancers, where CD28 agonistic binding on T cells and PSMA binding on tumor cells enhance anti-tumor activity at tumor sites.
Targeting tumor PSMA and CD28 binding using the described anti-CD28×anti-PSMA antibody formats.
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