Department of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
J Biol Chem. 2021 Jan-Jun;296:100116. doi: 10.1074/jbc.RA120.016234. Epub 2020 Dec 3.
CAR T cells targeting the B lymphocyte antigen CD19 have led to remarkable clinical results in B cell leukemia and lymphoma but eliminate all B lineage cells, leading to increased susceptibility to severe infections. As malignant B cells will express either immunoglobulin (Ig) light chain κ or λ, we designed a second-generation CAR targeting Igκ, IGK CAR. This construct demonstrated high target specificity but displayed reduced efficacy in the presence of serum IgG. Since CD19 CAR is insensitive to serum IgG, we designed various combinatorial CAR constructs in order to maintain the CD19 CAR T cell efficacy, but with IGK CAR target selectivity. The Kz-19BB design, combining CD19 CAR containing a 4-1BB costimulatory domain with an IGK CAR containing a CD3zeta stimulatory domain, maintained the target specificity of IgK CAR and was resistant to the presence of soluble IgG. Our results demonstrate that a combinatorial CAR approach can improve target selectivity and efficacy.
嵌合抗原受体 T 细胞（CAR T 细胞）靶向 B 淋巴细胞抗原 CD19，在 B 细胞白血病和淋巴瘤的治疗中取得了显著的临床效果，但同时也消除了所有 B 细胞谱系细胞，导致严重感染的易感性增加。由于恶性 B 细胞将表达免疫球蛋白（Ig）轻链 κ 或 λ，我们设计了靶向 Igκ 的第二代 CAR，即 IGK CAR。该构建体表现出高的靶特异性，但在存在血清 IgG 的情况下显示出降低的功效。由于 CD19 CAR 对血清 IgG 不敏感，我们设计了各种组合的 CAR 构建体，以在保持 CD19 CAR T 细胞功效的同时，具有 IGK CAR 的靶选择性。Kz-19BB 设计，将含有 4-1BB 共刺激结构域的 CD19 CAR 与含有 CD3zeta 刺激结构域的 IGK CAR 相结合，保持了 IGK CAR 的靶特异性，并能抵抗可溶性 IgG 的存在。我们的结果表明，组合 CAR 方法可以提高靶选择性和功效。
