Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought great advances to the treatment of acute lymphoblastic leukemia and B-cell lymphomas. However, relapse remains an issue in many cases. Such relapse can result from downregulation or loss of CD19 from the malignant cell population or expression of alternate isoforms. Consequently, there remains a need to target alternative B-cell antigens and diversify the spectrum of epitopes targeted within the same antigen. CD22 has been identified as a substitute target in cases of CD19-negative relapse. One anti-CD22 antibody—clone m971—targets a membrane-proximal epitope of CD22 and has been widely validated and used in the clinic. Here, we have compared m971-CAR with a novel CAR derived from IS7, an antibody that targets a central epitope on CD22. The IS7-CAR has superior avidity and is active and specific against CD22-positive targets, including B-acute lymphoblastic leukemia patient-derived xenograft samples. Side-by-side comparisons indicated that while IS7-CAR killed less rapidly than m971-CAR in vitro, it remains efficient in controlling lymphoma xenograft models in vivo. Thus, IS7-CAR presents a potential alternative candidate for the treatment of refractory B-cell malignancies.

嵌合抗原受体 (CAR) T 细胞疗法在治疗 B 细胞恶性肿瘤方面取得了相当大的成功。以B谱系标记物CD19为靶点，为急性淋巴细胞白血病和B细胞淋巴瘤的治疗带来了巨大进展。然而，在许多情况下，复发仍然是一个问题。这种复发可能是由于恶性细胞群中 CD19 的下调或丢失或替代亚型的表达所致。因此，仍然需要靶向替代 B 细胞抗原并使同一抗原内靶向的表位谱多样化。CD22 已被确定为 CD19 阴性复发病例的替代靶点。一种抗 CD22 抗体——克隆 m971——靶向 CD22 的近膜表位，并已在临床中得到广泛验证和使用。在这里，我们将 m971-CAR 与源自 IS7 的新型 CAR 进行了比较，IS7 是一种针对 CD22 上中心表位的抗体。IS7-CAR 具有卓越的亲和力，并且对 CD22 阳性靶点具有活性和特异性，包括 B 急性淋巴细胞白血病患者来源的异种移植样本。并列比较表明，虽然 IS7-CAR在体外的杀伤速度低于 m971-CAR，但它在体内控制淋巴瘤异种移植模型方面仍然有效。因此，IS7-CAR 为治疗难治性 B 细胞恶性肿瘤提供了潜在的替代候选药物。