Abayasiriwardana Keith, Wu Lei, Laklai Hanane, Nocula-Lugowska Malgorzata, Tchistiakova Lioudmila, Narula Jatin, Jackson-Fisher Amy, Golas Jonathon, Lam My-Hanh, Grinstein Veronika, Kang Jung Wook, Kearney Jessica C, Hosselet Christine, Upeslacis Erik, Lemon LuAnna, Zhang Yun, Ji Changhua, Buetow Bernard S, Finkelstein Martin B, Marshall Netonia, Bisulco Stephanie, Rosfjord Edward, Mathur Divya, Athanacio Jennifer, Thomas Ashley, Trageser Alexander, Fernandez Diane, Jiang Ziyue Karen, Ram Sripad, Cabral Edward, Manzuk Lisa, Maresca Kevin, Giddabasappa Anand, Lees Clare, Hooper Andrea T, Sapra Puja, Chintharlapalli Sudhakar
Oncology R&D, Pfizer Worldwide Research, San Diego, California.
Biomedicine Design, Pfizer Worldwide Research, Development and Medical, Cambridge, Massachusetts.
Mol Cancer Ther. 2025 Jul 2;24(7):976-992. doi: 10.1158/1535-7163.MCT-24-0379.
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.
免疫检查点抑制剂在乳腺癌（全球女性中最常见且致命的癌症）治疗中成效有限。新型免疫疗法，如靶向CD3的双特异性抗体，已在血液系统恶性肿瘤中展现出临床应用前景。然而，由于难以确定肿瘤特异性抗原，开发用于实体瘤的CD3双特异性抗体颇具挑战。B7-H4被认为是一种有吸引力的肿瘤相关抗原，可用于乳腺癌治疗，且对所有乳腺癌分子亚型均有广泛覆盖。我们设计了一种靶向B7-H4的CD3双特异性分子PF-07260437，并通过将细胞毒性T细胞导向乳腺癌细胞系，在体外证明了其依赖B7-H4的药理学作用。用PF-07260437治疗人乳腺癌的细胞系及患者来源的异种移植体内模型，可诱导显著的杀瘤活性，常导致完全缓解。从机制上讲，PF-07260437增加了T细胞数量并激活了T细胞，从而有效杀伤肿瘤。此外，在具有免疫活性的体内模型中，将PF-07260437与标准治疗方案（哌柏西利加氟维司群）及一种检查点抑制剂（抗PD-1）联合使用显示出协同效益。使用靶向CD8的示踪剂进行的临床相关非侵入性PET/CT成像显示，PF-07260437介导肿瘤内CD8 T细胞增加，凸显了CD8-PET技术在临床上潜在评估生物标志物变化的实用性。最后，食蟹猴的探索性毒理学研究突出了PF-07260437可控的毒性特征。这些数据支持对PF-07260437进行临床试验，以治疗表达B7-H4的实体瘤，包括乳腺癌。
