Cancer therapy involving an anti-PD1 antibody and a multi-specific binding protein that binds NKG2D, CD16, and a tumor-associated antigen
Inventors
Chang, Gregory P. • Cheung, Ann F. • Grinberg, Asya • GUTIERREZ, EVA • Haney, William • Wagtmann, Nicolai • LUNDE, Bradley M. • Prinz, Bianka
Assignees
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Publication Number
US-12384847-B2
Publication Date
2025-08-12
Expiration Date
Abstract
Combination therapy of a cancer with a multi-specific binding protein that bind a tumor associated antigen, the NKG2D receptor, and CD16, in combination with a second anti-cancer agent are described. Also described are pharmaceutical compositions of the multi-specific binding protein, and therapeutic methods useful for the treatment of cancer in combination with a second anti-cancer agent.
Core Innovation
The disclosed methods enhance tumor-cell death or treat a solid tumor using a multi-specific binding protein and an anti-PD-1 antibody. The protein binds and activates human NKG2D, binds a tumor-associated antigen, and comprises two heterodimeric human IgG1 Fc domains that together bind CD16. The tumor cell expresses the tumor-associated antigen on its surface, and the antigen-binding sites link to the N-termini of the respective Fc domains.
Reported studies describe natural killer cell activation, cytotoxicity, and tumor-cell lysis across variants targeting antigens including HER2, CD20, CD33, and BCMA, including targets with low antigen density or high CD64 expression. Antitumor activity and delayed tumor growth are documented for combinations with anti-PD-1 antibodies, producing increased responder mice in a B16F10 mouse model. The methods directly or indirectly enhance tumor-cell death and treat solid tumors expressing target antigens.
Claims Coverage
The provided claims identify two independent claims covering two inventive features directed to methods using a multi-specific binding protein and an anti-PD-1 antibody.
Enhancing tumor-cell death
The claim covers exposing a tumor cell and a natural killer cell to a multi-specific binding protein that binds and activates human NKG2D, binds a tumor-associated antigen, and comprises two human IgG1 Fc domains containing different amino acid mutations to promote heterodimerization that together bind CD16, wherein the tumor cell expresses the tumor-associated antigen on its surface and contacts an anti-PD-1 antibody.
Treating a solid tumor
The claim covers administering an effective amount of the multi-specific binding protein and an effective amount of an anti-PD-1 antibody to a subject in need thereof, wherein the protein binds and activates human NKG2D, binds a tumor-associated antigen, and comprises heterodimeric human IgG1 Fc domains that together bind CD16, with the antigen-binding sites linked to the N-termini of the Fc domains and the solid tumor expressing the tumor-associated antigen.
The independent claims cover methods for enhancing tumor-cell death and treating solid tumors expressing a tumor-associated antigen using the multi-specific binding protein in combination with an anti-PD-1 antibody.
Stated Advantages
The summary reports enhanced natural killer cell activation and tumor-cell lysis across HER2-, CD33-, and BCMA-directed constructs compared with controls, monoclonal antibodies, or bispecific comparators, including against low-antigen and CD64-high targets, with generally higher activity using cytokine- or drug-activated natural killer cells.
In the B16F10 mouse model, the combination of mcFAE-C26.99 and anti-PD-1 produced 40% responder mice, compared with 10% for either monotherapy, demonstrating delayed tumor growth and antitumor activity relative to controls.
The summary reports reduced target-cell or tumor-cell growth with HER2-TriNKET combined with pembrolizumab or a TLR agonist compared with controls, alongside improved survival with C26.99/mIL-12.
Documented Applications
Enhancing tumor-cell death directly or indirectly by exposing a tumor cell expressing a tumor-associated antigen and a natural killer cell to the multi-specific binding protein in combination with an anti-PD-1 antibody.
Treating solid tumors expressing a tumor-associated antigen on their surface using the multi-specific binding protein with an anti-PD-1 antibody, including breast, colorectal, gastric, renal cell, ovarian, pancreatic, prostate, and lung cancers, as well as melanoma, lymphomas, multiple myeloma, mesothelioma, and sarcomas.
Combination treatment of tumors using multi-specific proteins targeting tumor-associated antigens such as HER2, CD20, CD33, and BCMA with checkpoint blockers, particularly anti-PD-1 antibodies or TLR agonists, including in B16F10 melanoma models.
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