Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia.
Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia.
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DOI：
10.1136/jitc-2022-004850
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发表时间：
2022-11
影响因子：
10.9
通讯作者：
Rader, Christoph
中科院分区：
文献类型：
--
作者：
Cyr, Matthew G.;Mhibik, Maissa;Qi, Junpeng;Peng, Haiyong;Chang, Jing;Gaglione, Erika M.;Eik, David;Herrick, John;Venables, Thomas;Novick, Scott J.;Courouble, Valentine V.;Griffin, Patrick R.;Wiestner, Adrian;Rader, Christoph
尽管有许多治疗选择，但大多数慢性淋巴细胞白血病（CLL）患者无法获得安全和治愈性治疗。目前的治疗如抗-CD 20单克隆抗体（mAb）利妥昔单抗的缺点是消除所有健康的B细胞，导致体液免疫受损。我们先前报道了一种患者来源的CLL结合mAb JML-1的鉴定，并将唾液酸结合免疫球蛋白样凝集素-6（Siglec-6）鉴定为JML-1的靶标。尽管对Siglec-6知之甚少，但由于其在大多数健康细胞和组织中的缺失，它似乎是癌症免疫治疗的一个有吸引力的靶标。我们使用靶特异性方法来挖掘额外的患者来源的抗Siglec-6 mAb。为了评估在CLL的背景下靶向Siglec-6的治疗效用，将结合Siglec-6和CD 3的T细胞募集双特异性抗体（T-biAb）工程化到单链可变片段-Fc和双亲和力重靶向（DART）-Fc构建体中。评估T-biAb在体外、离体和体内的活性。我们发现了抗Siglec-6 mAb RC-1和RC-2，它们以比JML-1更高的亲和力结合，但保持相似的特异性。JML-1和RC-1 T-biAb均有效激活T细胞并杀死Siglec-6+靶细胞。DART-Fc形式的RC-1克隆是测试的最有效的T-biAb，并且是唯一的以病理性T与CLL细胞比率经由自体T细胞消除Siglec-6+原代CLL细胞的抗Siglec-6 T-biAb。在健康T细胞与B细胞比率下测试，它还消除了来自健康供体的原代B细胞的Siglec-6+部分。DART-Fc形式的亚皮摩尔效力归因于溶细胞突触的长度和柔性的减少。此外，RC-1 T-biAb在体内有效清除MEC 1 CLL细胞，并显示循环半衰期超过7天。Siglec-6靶向T-biAb对消除Siglec-6+白血病和健康B细胞具有高度效力和特异性，同时保留Siglec-6−健康B细胞，这表明了一种独特的CLL治疗策略，减少了体液免疫抑制。我们的数据证实了T-biAb功效取决于突触几何形状的报道，并揭示了突触结构可以通过抗体工程来调节。我们的全人抗Siglec-6抗体和T-biAb具有癌症免疫治疗的潜力。NCT00923507。
Despite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the anti-CD20 monoclonal antibody (mAb) rituximab is the elimination of all healthy B cells, resulting in impaired humoral immunity. We previously reported the identification of a patient-derived, CLL-binding mAb, JML-1, and identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) as the target of JML-1. Although little is known about Siglec-6, it appears to be an attractive target for cancer immunotherapy due to its absence on most healthy cells and tissues. We used a target-specific approach to mine for additional patient-derived anti-Siglec-6 mAbs. To assess the therapeutic utility of targeting Siglec-6 in the context of CLL, T cell-recruiting bispecific antibodies (T-biAbs) that bind to Siglec-6 and CD3 were engineered into single-chain variable fragment–Fc and dual-affinity retargeting (DART)–Fc constructs. T-biAbs were evaluated for their activity in vitro, ex vivo, and in vivo. We discovered the anti-Siglec-6 mAbs RC-1 and RC-2, which bind with higher affinity than JML-1 yet maintain similar specificity. Both JML-1 and RC-1 T-biAbs were effective at activating T cells and killing Siglec-6+ target cells. The RC-1 clone in the DART–Fc format was the most potent T-biAb tested and was the only anti-Siglec-6 T-biAb that eliminated Siglec-6+ primary CLL cells via autologous T cells at pathological T-to-CLL cell ratios. Tested at healthy T-to-B cell ratios, it also eliminated a Siglec-6+ fraction of primary B cells from healthy donors. The subpicomolar potency of the DART–Fc format was attributed to the reduction in the length and flexibility of the cytolytic synapse. Furthermore, the RC-1 T-biAb was effective at clearing MEC1 CLL cells in vivo and demonstrated a circulatory half-life of over 7 days. Siglec-6-targeting T-biAbs are highly potent and specific for eliminating Siglec-6+ leukemic and healthy B cells while sparing Siglec-6− healthy B cells, suggesting a unique treatment strategy for CLL with diminished suppression of humoral immunity. Our data corroborate reports that T-biAb efficacy is dependent on synapse geometry and reveal that synapse architecture can be tuned via antibody engineering. Our fully human anti-Siglec-6 antibodies and T-biAbs have potential for cancer immunotherapy. NCT00923507.
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影响因子：
6.8
作者：
Marciano, David P.;Dharmarajan, Venkatasubramanian;Griffin, Patrick R.
通讯作者：
Griffin, Patrick R.
影响因子：
5.7
作者：
Calissano, Carlo;Damle, Rajendra N.;Chiorazzi, Nicholas
通讯作者：
Chiorazzi, Nicholas
影响因子：
5.4
作者：
Benmerzoug, Sulayman;Chevalier, Mathieu F.;Derre, Laurent
通讯作者：
Derre, Laurent
DOI：
10.1126/science.abc8697
发表时间：
2021-03-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsiue EH;Wright KM;Douglass J;Hwang MS;Mog BJ;Pearlman AH;Paul S;DiNapoli SR;Konig MF;Wang Q;Schaefer A;Miller MS;Skora AD;Azurmendi PA;Murphy MB;Liu Q;Watson E;Li Y;Pardoll DM;Bettegowda C;Papadopoulos N;Kinzler KW;Vogelstein B;Gabelli SB;Zhou S
通讯作者：
Zhou S
影响因子：
5.6
作者：
Johnson, Syd;Burke, Stephen;Bonvini, Ezio
通讯作者：
Bonvini, Ezio