Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release.
Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release.
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DOI：
10.1136/jitc-2021-002488
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发表时间：
2021-06
影响因子：
10.9
通讯作者：
Dalvi P
中科院分区：
文献类型：
--
作者：
Dang K;Castello G;Clarke SC;Li Y;Balasubramani A;Boudreau A;Davison L;Harris KE;Pham D;Sankaran P;Ugamraj HS;Deng R;Kwek S;Starzinski A;Iyer S;van Schooten W;Schellenberger U;Sun W;Trinklein ND;Buelow R;Buelow B;Fong L;Dalvi P
目前可用于转移性去势抵抗性前列腺癌 (mCRPC) 的治疗方案不能将中位总生存期延长超过 6 个月。因此，开发针对 mCRPC 的新型有效疗法是迫切的医疗需求。由于其靶向作用机制，T 细胞接合剂 (TCE) 已成为治疗 mCRPC 的一种有前途的方法。然而，由于迄今为止观察到的 TCE 在实体瘤中的疗效有限，以及由于使用高亲和力抗 CD3 部分（如 OKT3）而导致与细胞因子释放综合征（CRS）相关的毒性，临床仍面临挑战。使用表达完全人 IgG 抗体的基因工程转基因大鼠（UniRat 和 OmniFlic）以及基于 NGS 的抗体发现管道，我们开发了 TNB-585，这是一种用于治疗 mCRPC 的抗 CD3xPSMA TCE。 TNB-585 以双特异性形式将肿瘤靶向抗 PSMA 臂与独特的低亲和力抗 CD3 臂配对。我们在二维 (2D) 培养物和三维 (3D) 球体中针对 PSMA+ 肿瘤细胞以及针对患者来源的前列腺肿瘤细胞的 T 细胞重定向细胞毒性测定中测试了 TNB-585。测量培养物上清液中的细胞因子，以评估 TNB-585 以低细胞因子释放诱导肿瘤杀伤的能力。测量 TNB-585 介导的 T 细胞活化、增殖和细胞毒性颗粒形成，以研究其作用机制。此外，还针对 C4-2 荷瘤 NCG 小鼠体内评估了 TNB-585 的功效。在体外，TNB-585 诱导人类 T 细胞的激活和增殖，从而杀死 2D 培养物和 3D 球体中的 PSMA+ 前列腺肿瘤细胞，与包含相同抗 PSMA 臂但具有更高亲和力的抗 CD3 臂（与 OKT3 相当）的阳性对照抗体相比，细胞因子释放最少，调节性 T 细胞激活减少。此外，TNB-585 在体外表现出对患者来源的前列腺肿瘤的有效功效，并在体内诱导免疫细胞浸润和剂量依赖性肿瘤消退。我们的数据表明，与包含高亲和力抗 CD3 结构域的 TCE 相比，具有低亲和力抗 CD3 结构域的 TNB-585 可能有效，同时降低前列腺癌患者 CRS 的发生率和严重程度。
Therapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3. Using genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice. In vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo. Our data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.
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DOI：
10.1084/jem.173.6.1483
发表时间：
1991-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Canfield SM;Morrison SL
通讯作者：
Morrison SL
影响因子：
--
作者：
Marshall, Catherine Handy;Antonarakis, Emmanuel S
通讯作者：
Antonarakis, Emmanuel S
影响因子：
4.8
作者：
Patrikidou, A.;Loriot, Y.;Fizazi, K.
通讯作者：
Fizazi, K.
DOI：
10.1093/protein/9.7.617
发表时间：
1996-07-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Ridgway, JBB;Presta, LG;Carter, P
通讯作者：
Carter, P
影响因子：
2.8
作者：
Hummel, Horst-Dieter;Kufer, Peter;Bargou, Ralf C.
通讯作者：
Bargou, Ralf C.