An engineered NKp46 antibody for construction of multi-specific NK cell engagers.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Robert B Lee, Sainiteesh Maddineni, Madeleine Landry, Celeste Diaz, Aanya Tashfeen, Sean A Yamada-Hunter, Crystal L Mackall, Corinne Beinat, John B Sunwoo, Jennifer R Cochran
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Abstract

Recent developments in cancer immunotherapy have highlighted the potential of harnessing natural killer (NK) cells in the treatment of neoplastic malignancies. Of these, bispecific antibodies, and NK cell engager (NKCE) protein therapeutics in particular, have been of interest. Here, we used phage display and yeast surface display to engineer RLN131, a unique cross-reactive antibody that binds to human, mouse, and cynomolgus NKp46, an activating receptor found on NK cells. RLN131 induced proliferation and activation of primary NK cells, and was used to create bispecific NKCE constructs of varying configurations and valency. All NKCEs were able to promote greater NK cell cytotoxicity against tumor cells than an unmodified anti-CD20 monoclonal antibody, and activity was observed irrespective of whether the constructs contained a functional Fc domain. Competition binding and fine epitope mapping studies were used to demonstrate that RLN131 binds to a conserved epitope on NKp46, underlying its species cross-reactivity.

用于构建多特异性 NK 细胞吞噬体的工程化 NKp46 抗体。
癌症免疫疗法的最新发展突显了利用自然杀伤(NK)细胞治疗肿瘤恶性肿瘤的潜力。其中,双特异性抗体和NK细胞吞噬蛋白疗法尤其受到关注。在这里,我们利用噬菌体展示和酵母表面展示技术设计出了一种独特的交叉反应抗体RLN131,它能与人类、小鼠和犬科动物的NKp46结合,NKp46是NK细胞上的一种激活受体。RLN131 能诱导原代 NK 细胞的增殖和活化,并被用于制造不同构型和效价的双特异性 NCKE 构合物。与未修饰的抗 CD20 单克隆抗体相比,所有 NCKE 都能增强 NK 细胞对肿瘤细胞的细胞毒性,而且无论构建物是否含有功能性 Fc 结构域,都能观察到其活性。竞争结合和精细表位图谱研究证明,RLN131 与 NKp46 上的保守表位结合,是其物种交叉反应性的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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