University of Groningen, University Medical Center Groningen, Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen, Department of Hematology, Section Immunohematology, Groningen, The Netherlands.
J Invest Dermatol. 2019 Nov;139(11):2343-2351.e3. doi: 10.1016/j.jid.2019.01.038. Epub 2019 May 23.
Reactivation of functionally-impaired anticancer T cells by programmed cell death protein 1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1)-blocking antibodies shows prominent therapeutic benefit in advanced melanoma and patients with non-small cell lung cancer. However, current PD-L1-blocking antibodies lack intrinsic tumor selectivity. Therefore, efficacy may be reduced resulting from on-target and off-tumor binding to PD-L1-expressing normal cells. This may lead to indiscriminate activation of antigen-experienced T cells, including those implicated in autoimmune-related adverse events. To direct PD-L1 blockade to chondroitin sulfate proteoglycan 4 (CSPG4)-expressing cancers and to reactivate anticancer T cells more selectively, we constructed bispecific antibody PD-L1xCSPG4. CSPG4 is an established target antigen that is selectively overexpressed on malignant melanoma and various other difficult-to-treat cancers. PD-L1xCSPG4 showed enhanced capacity for CSPG4-directed blockade of PD-L1 on cancer cells. Importantly, treatment of mixed cultures containing primary patient-derived CSPG4-expressing melanoma cells and autologous tumor-infiltrating lymphocytes with PD-L1xCSPG4 significantly enhanced activation status, IFN-γ production, and cytolytic activity of anticancer T cells. In conclusion, tumor-directed blockade of PD-L1 by PD-L1xCSPG4 may improve efficacy and safety of PD-1/PD-L1 checkpoint blockade for treatment of melanoma and other CSPG4-overexpressing malignancies.
程序性细胞死亡蛋白 1（PD-1）和程序性细胞死亡受体配体 1（PD-L1）阻断抗体可重新激活功能失调的抗癌 T 细胞，在晚期黑色素瘤和非小细胞肺癌患者中显示出显著的治疗益处。然而，目前的 PD-L1 阻断抗体缺乏内在的肿瘤选择性。因此，由于与表达 PD-L1 的正常细胞的靶内和靶外结合，疗效可能会降低。这可能导致抗原经验丰富的 T 细胞的无差别激活，包括那些与自身免疫相关的不良事件有关的 T 细胞。为了将 PD-L1 阻断靶向到硫酸软骨素蛋白聚糖 4（CSPG4）表达的癌症，并更选择性地重新激活抗癌 T 细胞，我们构建了双特异性抗体 PD-L1xCSPG4。CSPG4 是一种已确立的靶抗原，在恶性黑色素瘤和各种其他难以治疗的癌症中选择性过表达。PD-L1xCSPG4 显示出增强的 CSPG4 导向阻断癌细胞上 PD-L1 的能力。重要的是，用 PD-L1xCSPG4 治疗含有源自患者的表达 CSPG4 的黑色素瘤细胞和自体肿瘤浸润淋巴细胞的混合培养物，显著增强了抗癌 T 细胞的激活状态、IFN-γ 产生和细胞毒性活性。总之，PD-L1xCSPG4 通过肿瘤靶向阻断 PD-L1 可能提高 PD-1/PD-L1 检查点阻断治疗黑色素瘤和其他 CSPG4 过表达恶性肿瘤的疗效和安全性。
