A Novel B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies

Immune checkpoint inhibitors have shown limited success in breast cancer, the most common and deadly cancer in women worldwide. Novel immune therapies, such as CD3-engaging bispecific antibodies, have shown clinical promise in hematologic malignancies. However, developing CD3 bispecifics for solid tumors has been challenging due to the difficulty in identifying tumor-specific antigens. B7-H4 is proposed as an attractive tumor-associated antigen for breast cancer therapeutics with comprehensive coverage regardless of breast cancer molecular subtype. We designed a B7-H4-targeting CD3 bispecific molecule, PF-07260437, and demonstrated B7-H4-dependent pharmacology in vitro by directing cytotoxic T-cell killing to breast cancer cell lines. Treatment of cell line- and patient-derived xenograft in vivo models of human breast cancer with PF-07260437 induced substantial tumoricidal activity, often resulting in complete responses. Mechanistically, PF-07260437 increased T-cell number and activation, leading to efficient tumor killing. Additionally, combining PF-07260437 with standard of care (palbociclib plus fulvestrant) and a checkpoint inhibitor (anti-PD-1) showed combinatorial benefits in an immune-competent in vivo model. Clinically relevant noninvasive PET/CT imaging with a CD8-targeting tracer demonstrated PF-07260437-mediated increases in intratumoral CD8 T cells, highlighting the utility of CD8-PET technology to potentially assess biomarker changes in the clinic. Finally, the manageable toxicity profile of PF-07260437 was highlighted in an exploratory toxicology study in cynomolgus monkeys. These data support the clinical testing of PF-07260437 for treating B7-H4-expressing solid tumors, including breast cancer.

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Publication Details

Journal
Molecular Cancer Therapeutics
Published
2025-05-14
DOI
https://doi.org/10.1158/1535-7163.mct-24-0379
Citations
2
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
2.09
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article

A Novel B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies

Keith Abayasiriwardana, Hanane Laklai, Divya Mathur, Kevin Maresca et al.
2 citations
Molecular Cancer Therapeutics
CAR-T cell therapy research
2.09
article

A Novel B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies

Keith Abayasiriwardana, Hanane Laklai, Divya Mathur, Kevin Maresca, Andrea T. Hooper, Anand Giddabasappa, Sudhakar Chintharlapalli, LuAnna Lemon, Jatin Narula, Puja Sapra, Jonathon Golas, Christine Hosselet, Edward Cabral, Changhua Ji, Bernard S. Buetow, Lisa K. Manzuk, Veronika Grinstein, Diane R. Fernandez, Małgorzata Nocula‐Ługowska, Jennifer Athanacio, Lioudmila Tchistiakova, Netonia Marshall, Amy Jackson-Fisher, My‐Hanh Lam, Edward Rosfjord, Stephanie Bisulco, Lei Wu, Jung Wook Kang, Sripad Ram, Erik Upeslacis, Ziyue Karen Jiang, Clare Lees, Ashley Thomas, Martin B. Finkelstein, Jessica C. Kearney, Yun Zhang, Alexander Trageser
article en
2 citations

Abstract

Immune checkpoint inhibitors have shown limited success in breast cancer, the most common and deadly cancer in women worldwide. Novel immune therapies, such as CD3-engaging bispecific antibodies, have shown clinical promise in hematologic malignancies. However, developing CD3 bispecifics for solid tumors has been challenging due to the difficulty in identifying tumor-specific antigens. B7-H4 is proposed as an attractive tumor-associated antigen for breast cancer therapeutics with comprehensive coverage regardless of breast cancer molecular subtype. We designed a B7-H4-targeting CD3 bispecific molecule, PF-07260437, and demonstrated B7-H4-dependent pharmacology in vitro by directing cytotoxic T-cell killing to breast cancer cell lines. Treatment of cell line- and patient-derived xenograft in vivo models of human breast cancer with PF-07260437 induced substantial tumoricidal activity, often resulting in complete responses. Mechanistically, PF-07260437 increased T-cell number and activation, leading to efficient tumor killing. Additionally, combining PF-07260437 with standard of care (palbociclib plus fulvestrant) and a checkpoint inhibitor (anti-PD-1) showed combinatorial benefits in an immune-competent in vivo model. Clinically relevant noninvasive PET/CT imaging with a CD8-targeting tracer demonstrated PF-07260437-mediated increases in intratumoral CD8 T cells, highlighting the utility of CD8-PET technology to potentially assess biomarker changes in the clinic. Finally, the manageable toxicity profile of PF-07260437 was highlighted in an exploratory toxicology study in cynomolgus monkeys. These data support the clinical testing of PF-07260437 for treating B7-H4-expressing solid tumors, including breast cancer.

Molecular Cancer TherapeuticsVol. 24(7)
Pfizer (United States) (US), Regeneron (United States) (US), Third Dimension Technologies (United States) (US), AstraZeneca (United States) (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 12%
CAR-T cell therapy research
2.09
DOIOpen Access PDFOpenAlex
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