Rationally targeted anti-VISTA antibody that blockades the C-C' loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner.
Rationally targeted anti-VISTA antibody that blockades the C-C' loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner.
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DOI：
10.1136/jitc-2021-003382
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
D Boyd-Kirkup J
中科院分区：
文献类型：
--
作者：
Thakkar D;Paliwal S;Dharmadhikari B;Guan S;Liu L;Kar S;Tulsian NK;Gruber JJ;DiMascio L;Paszkiewicz KH;Ingram PJ;D Boyd-Kirkup J
尽管近年来癌症免疫治疗取得了重大进展，但对现有免疫检查点疗法（ICT）的耐药性很常见。T细胞活化的v域Ig抑制因子（VISTA）是一种主要的髓系免疫检查点调节因子，由于其在髓系富集的肿瘤微环境中抑制促炎抗肿瘤反应的作用，它代表了一个有希望的治疗靶点。然而，同源VISTA配体的不确定性使得开发有效的抗VISTA抗体具有挑战性。VISTA在正常免疫细胞亚型上的表达支持一种中和性非消耗抗体，然而，先前报道的抗VISTA抗体使用IgG1 Fc同型，通过抗体依赖的细胞毒性/补体依赖的细胞毒性来消耗VISTA+细胞，这些抗体显示出快速的血清清除和免疫毒性。在这里，我们使用了一种合理的抗体发现方法来开发第一个不依赖fc的抗vista抗体HMBD-002，它结合了计算预测的c- c环内的功能表位，与其他已知的抗vista抗体不同。该表位是物种保守的，允许HMBD-002在人类和小鼠免疫激活模型和癌症模型（包括人源化小鼠模型）中进行强大的体外和体内测试。我们在这里证明，HMBD-002的阻断抑制了VISTA与潜在伴侣的结合，包括V-Set和含有3的免疫球蛋白结构域，以减少骨髓源性的T细胞活性抑制和阻止中性粒细胞迁移。免疫细胞环境分析表明，HMBD-002治疗刺激了以Th1/Th17反应为特征的促炎表型，再现了以前在VISTA敲除模型中注意到的表型。这一作用机制进一步得到了免疫能力强的结肠直肠癌、乳腺癌和肺癌小鼠模型和人源化小鼠模型的支持，在不消耗VISTA表达细胞的情况下，中和VISTA可显著抑制肿瘤生长，同时减少抑制性骨髓细胞的浸润，增加T细胞活性。最后，我们没有观察到IgG1抗体的快速血清清除或免疫毒性。综上所述，我们已经证明，通过用一种一流的合理靶向且非耗损的IgG4同型抗VISTA抗体HMBD-002阻断VISTA的功能性C-C '环区域，可以逆转VISTA诱导的免疫抑制。该抗体在vista抑制的ICT无应答人群中代表了一种非常有前途的新疗法。
Despite significant progress in cancer immunotherapy in recent years, resistance to existing immune checkpoint therapies (ICT) is common. V-domain Ig suppressor of T cell activation (VISTA), a predominantly myeloid immune checkpoint regulator, represents a promising therapeutic target due to its role in suppressing proinflammatory antitumor responses in myeloid-enriched tumor microenvironments. However, uncertainty around the cognate VISTA ligand has made the development of effective anti-VISTA antibodies challenging. The expression of VISTA on normal immune cell subtypes argues for a neutralizing non-depleting antibody, however, previous reported anti-VISTA antibodies use IgG1 Fc isotypes that deplete VISTA+ cells by antibody dependent cellular cytotoxicity/complement dependent cytotoxicity and these antibodies have shown fast serum clearance and immune toxicities. Here we used a rational antibody discovery approach to develop the first Fc-independent anti-VISTA antibody, HMBD-002, that binds a computationally predicted functional epitope within the C-C-loop, distinct from other known anti-VISTA antibodies. This epitope is species-conserved allowing robust in vitro and in vivo testing of HMBD-002 in human and murine models of immune activation and cancer including humanized mouse models. We demonstrate here that blockade by HMBD-002 inhibits VISTA binding to potential partners, including V-Set and Immunoglobulin domain containing 3, to reduce myeloid-derived suppression of T cell activity and prevent neutrophil migration. Analysis of immune cell milieu suggests that HMBD-002 treatment stimulates a proinflammatory phenotype characterized by a Th1/Th17 response, recapitulating a phenotype previously noted in VISTA knockout models. This mechanism of action is further supported by immune-competent syngenic and humanized mouse models of colorectal, breast and lung cancer where neutralizing VISTA, without depleting VISTA expressing cells, significantly inhibited tumor growth while decreasing infiltration of suppressive myeloid cells and increasing T cell activity. Finally, we did not observe either the fast serum clearance or immune toxicities that have been reported for IgG1 antibodies. In conclusion, we have shown that VISTA-induced immune suppression can be reversed by blockade of the functional C-C’ loop region of VISTA with a first-in-class rationally targeted and non-depleting IgG4 isotype anti-VISTA antibody, HMBD-002. This antibody represents a highly promising novel therapy in the VISTA-suppressed ICT non-responder population.
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影响因子：
11.2
作者：
Le Mercier I;Chen W;Lines JL;Day M;Li J;Sergent P;Noelle RJ;Wang L
通讯作者：
Wang L
影响因子：
82.9
作者：
Gao J;Ward JF;Pettaway CA;Shi LZ;Subudhi SK;Vence LM;Zhao H;Chen J;Chen H;Efstathiou E;Troncoso P;Allison JP;Logothetis CJ;Wistuba II;Sepulveda MA;Sun J;Wargo J;Blando J;Sharma P
通讯作者：
Sharma P
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
7.3
作者：
Broughton, Thomas W. K.;ElTanbouly, Mohamed A.;Lines, J. Louise
通讯作者：
Lines, J. Louise
影响因子：
4.6
作者：
Mehta, Nishant;Maddineni, Sainiteesh;Cochran, Jennifer R.
通讯作者：
Cochran, Jennifer R.