Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor-specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Mice expressing the human extracellular regions of CD3 and PSMA were generated to examine antitumor efficacy in the presence of an intact immune system and PSMA expression in normal tissues. PSMAxCD3 accumulated in PSMA-expressing tissues and tumors as detected by immuno-PET imaging. Although PSMAxCD3 induced T-cell activation and showed antitumor efficacy in mice with low tumor burden, PSMAxCD3 lost efficacy against larger solid tumors, mirroring the difficulty of treating solid tumors in the clinic. Costimulatory receptors can enhance T-cell responses. We show here that costimulation can enhance the antitumor efficacy of PSMAxCD3. In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors.

中文翻译：

---

靶向PSMA的CD3双特异性抗体诱导抗肿瘤反应，该反应被4-1BB共刺激增强。

血液肿瘤患者用双特异性抗体治疗后可改善结局，该双特异性抗体与T细胞上的CD3结合并将T细胞重定向至癌细胞。然而，针对实体瘤的临床益处仍有待显示。我们制得了一种针对共同的前列腺肿瘤特异性抗原PSMA和CD3（PMSAxCD3）的双特异性抗体，并为几种临床前实体瘤模型中的肿瘤抑制提供了证据。产生表达CD3和PSMA的人细胞外区域的小鼠，以检查在完整的免疫系统和正常组织中PSMA表达的存在下的抗肿瘤功效。免疫PET成像检测到PSMAxCD3积累在表达PSMA的组织和肿瘤中。尽管PSMAxCD3诱导T细胞活化并在低肿瘤负荷的小鼠中显示出抗肿瘤功效，PSMAxCD3对较大的实体瘤失去效力，这反映了临床上治疗实体瘤的困难。共刺激受体可以增强T细胞反应。我们在这里表明，协同刺激可以增强PSMAxCD3的抗肿瘤功效。特别地，4-1BB刺激与PSMAxCD3的结合增强了T细胞的活化和增殖，增强了对抗较大肿瘤的功效，并诱导了T细胞记忆，从而导致了持久的抗肿瘤反应。CD3双特异性抗体和抗4-1BB共刺激的组合代表了一种治疗实体瘤的治疗方法。4-1BB刺激与PSMAxCD3结合可增强T细胞活化和增殖，增强抗较大肿瘤的功效，并诱导T细胞记忆，从而导致持久的抗肿瘤反应。CD3双特异性抗体和抗4-1BB共刺激的组合代表了一种治疗实体瘤的治疗方法。4-1BB刺激与PSMAxCD3结合可增强T细胞活化和增殖，增强抗较大肿瘤的功效，并诱导T细胞记忆，从而导致持久的抗肿瘤反应。CD3双特异性抗体和抗4-1BB共刺激的组合代表了一种治疗实体瘤的治疗方法。