Department of Radiation Oncology, Stanford University, Stanford, CA.
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX.
J Exp Med. 2022 Sep 5;219(9). doi: 10.1084/jem.20220214. Epub 2022 Jul 26.
Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.
血液系统恶性肿瘤患者的疾病复发和治疗引起的免疫毒性带来了重大的临床挑战。在这里，我们揭示了中和 TNF 受体配体 APRIL 和 BAFF 及其在 MM 和 DLBCL 中的受体活性的独特需求，影响 MM 细胞中的蛋白质翻译和产生，并调节 ATM 相互作用蛋白（ATMIN/ACSIZ）的翻译效率。在治疗方面，我们研究了使用 BCMA 诱饵受体（sBCMA-Fc）作为 APRIL 和 BAFF 的抑制剂。虽然野生型 sBCMA-Fc 可有效阻断 MM 中的 APRIL 信号传导，但由于其与 BAFF 的结合较弱，在 DLBCL 中缺乏活性。为了扩大 sBCMA-Fc 的治疗用途，我们设计了一种亲和力增强的突变体 sBCMA-Fc 融合分子（sBCMA-Fc V3），其与 APRIL 和 BAFF 的结合能力分别增强了 4 倍和 500 倍。突变体 sBCMA-Fc V3 克隆显著增强了对 MM 和 DLBCL 的抗肿瘤活性。重要的是，我们还在非人类灵长类动物研究中证明了足够的毒性概况和针对目标的作用机制。
