Espinosa-Cotton Madelyn, Hoseini Sayed Shahabuddin, Miranda Ileana C, Herrick John, Cheung Nai-Kong V
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Blood Adv. 2025 Jan 14;9(1):116-126. doi: 10.1182/bloodadvances.2022009187.
Allogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft-versus-host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5% to 30% for severe cases. In this manuscript, we describe a tetravalent T-cell-engaging bispecific antibody (BsAb) based on the immunoglobulin G-[L]-single-chain variable fragment (IgG-[L]-scFv) platform, with all 4 binding domains specific for CD3. In vitro, picomolar concentrations of the CD3×CD3 BsAb induced potent lysis of activated CD4 and CD8 T cells. In immunodeficient mice, in which human T cells induced xenogeneic GVHD, administration of 0.1 μg BsAb per dose depleted the majority of T cells from the peripheral blood, and 10 μg per dose completely reversed established GVHD and achieved a 100% survival rate. In mice bearing NALM6-luc xenografts, treatment with CD3×CD19 BsAb and activated human T cells induced complete remission of the leukemia, and all treated mice developed GVHD by 50 days after treatment. CD3×CD3 BsAb (3-30 μg doses) reversed clinical signs of GVHD, allowing long term follow-up beyond 250 days. T cells were undetectable by polymerase chain reaction in 4 of 5 mice in the 30 μg CD3×CD3 BsAb group 180 days after leukemia injection, and complete necropsies on day 259 revealed no evidence of human T cells or leukemia cells. Curing GVHD allows for long-term follow-up of tumor response heretofore impossible in humanized mouse models. Further studies are warranted to determine whether the CD3×CD3 BsAb has potential for treating clinical GVHD and other autoimmune diseases in humans.
异基因造血干细胞移植是治疗血液系统恶性肿瘤和某些遗传性疾病的既定疗法。急性移植物抗宿主病（GVHD）是最常见且使人虚弱的副作用，严重病例的生存率低至5%至30%。在本论文中，我们描述了一种基于免疫球蛋白G-[L]-单链可变片段（IgG-[L]-scFv）平台的四价T细胞结合双特异性抗体（BsAb），其所有4个结合域均对CD3具有特异性。在体外，皮摩尔浓度的CD3×CD3 BsAb可诱导活化的CD4和CD8 T细胞发生有效裂解。在人T细胞诱导异种GVHD的免疫缺陷小鼠中，每剂给予0.1μg BsAb可使外周血中的大多数T细胞耗竭，每剂给予10μg可完全逆转已确立的GVHD并实现100%的生存率。在携带NALM6-luc异种移植物的小鼠中，用CD3×CD19 BsAb和活化的人T细胞进行治疗可诱导白血病完全缓解，且所有接受治疗的小鼠在治疗后50天内均发生了GVHD。CD3×CD3 BsAb（3 - 30μg剂量）可逆转GVHD的临床症状，使长期随访超过250天成为可能。在白血病注射后180天，30μg CD3×CD3 BsAb组的5只小鼠中有4只通过聚合酶链反应检测不到T细胞，在第259天进行的完整尸检未发现人T细胞或白血病细胞的证据。治愈GVHD使得在人源化小鼠模型中对肿瘤反应进行前所未有的长期随访成为可能。有必要进一步研究以确定CD3×CD3 BsAb是否具有治疗人类临床GVHD和其他自身免疫性疾病的潜力。
