We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 μg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33-expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD-1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 μg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together, MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Mol Cancer Ther; 17(8); 1761–72. ©2018 AACR.

中文翻译：

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开发 MGD007，一种 gpA33 x CD3 双特异性 DART® 蛋白，用于转移性结直肠癌的 T 细胞免疫治疗

我们开发了 MGD007（抗糖蛋白 A33 x 抗 CD3），这是一种 DART 蛋白，旨在将 T 细胞重定向到表达 gpA33 的结肠癌。gpA33 靶标是在基于抗体的筛选的基础上选择的，以识别在原发性和转移性结直肠癌标本中普遍表达的癌症抗原，包括推定的癌症干细胞群。MGD007 显示出预期的双特异性结合特性，并通过募集 T 细胞介导 gpA33 阳性癌细胞系（包括结直肠癌干细胞模型）的有效裂解。异种移植研究表明，低至 4 μg/kg 的剂量可抑制肿瘤生长。CD8 和 CD4 T 细胞均介导表达 gpA33 的肿瘤细胞的裂解，其活性伴随着颗粒酶和穿孔素的增加。尤其，抑制性 T 细胞群也可用于介导表达 gpA33 的肿瘤细胞的裂解。伴随 CTL 活性，T 细胞活化和扩增均以 gpA33 依赖性方式观察到。单独使用人 PBMC 未观察到细胞因子激活，这与外周血细胞群中不存在 gpA33 表达一致。在长期暴露于 MGD007 和 gpA33 阳性肿瘤细胞后，T 细胞表达 PD-1 和 LAG-3 并获得记忆表型，但保留支持有效细胞杀伤的能力。在食蟹猴中，每周 4 次 100 μg/kg 的剂量耐受性良好，延长的 PK 与含 Fc 的分子一致。综合起来，MGD007 显示出对结直肠癌细胞的有效活性，与其设计赋予的作用机制一致，并支持进一步研究 MGD007 作为结直肠癌潜在的新型治疗方法。摩尔癌症治疗; 17(8); 1761-72 年。©2018 AACR。