研究人员开发出了一种通用的方法来隐蔽抗体的结合域。该方法是通过异二聚体卷曲螺旋结构域在空间上闭塞互补决定区域。当这种卷曲螺旋肽暴露于肿瘤相关蛋白酶，如基质金属蛋白酶-2和-9时，卷曲螺旋肽被这些酶所裂解，抗原结合能力得到恢复。课题组测试了多种卷曲螺旋样式，证明优化的隐藏域广泛适用于感兴趣的抗体。该方法可以防止小鼠体内抗CD3相关细胞因子的释放，并通过保护抗体不受抗原库的影响，显著提高其循环半衰期。在小鼠癌症模型中，研究者将该方法应用于抗体-药物偶联物，发现隐蔽抗体优先在肿瘤部位发生去隐蔽反应。与未隐蔽抗体相比，该隐蔽抗体具有更好的抗肿瘤效果。

据介绍，单克隆抗体对健康组织的交叉反应性限制了其在癌症治疗中的应用。通过在肿瘤微环境中产生选择性激活的隐蔽抗体，肿瘤靶向性得到了提高，但每一种隐蔽抗体都需要进行定制设计。

附：英文原文

Title: A coiled-coil masking domain for selective activation of therapeutic antibodies

Author: Vivian H. Trang, Xinqun Zhang, Roma C. Yumul, Weiping Zeng, Ivan J. Stone, Serena W. Wo, Melissa M. Dominguez, Julia H. Cochran, Jessica K. Simmons, Maureen C. Ryan, Robert P. Lyon, Peter D. Senter, Matthew R. Levengood

Issue&Volume: Volume 37 Issue 7, July 2019

Abstract: The use of monoclonal antibodies in cancer therapy is limited by their cross-reactivity to healthy tissue. Tumor targeting has been improved by generating masked antibodies that are selectively activated in the tumor microenvironment, but each such antibody necessitates a custom design. Here, we present a generalizable approach for masking the binding domains of antibodies with a heterodimeric coiled-coil domain that sterically occludes the complementarity-determining regions. On exposure to tumor-associated proteases, such as matrix metalloproteinases 2 and 9, the coiled-coil peptides are cleaved and antigen binding is restored. We test multiple coiled-coil formats and show that the optimized masking domain is broadly applicable to antibodies of interest. Our approach prevents anti-CD3-associated cytokine release in mice and substantially improves circulation half-life by protecting the antibody from an antigen sink. When applied to antibodydrug conjugates, our masked antibodies are preferentially unmasked at the tumor site and have increased anti-tumor efficacy compared with unmasked antibodies in mouse models of cancer.

DOI: 10.1038/s41587-019-0135-x

Source:https://www.nature.com/articles/s41587-019-0135-x