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 co-stimulatory domain with an IGK CAR containing a CD3zeta stimulatory domain, maintained the target specificity of IgK CAR and was resistant to the presence of sIgG. Our results demonstrate that a combinatorial CAR approach can improve target selectivity and efficacy.

中文翻译：

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组合CAR设计改善目标限制


靶向 B 淋巴细胞抗原 CD19 的 CAR T 细胞在 B 细胞白血病和淋巴瘤方面取得了显着的临床效果，但消除了所有 B 谱系细胞，导致严重感染的易感性增加。由于恶性B细胞会表达免疫球蛋白（Ig）轻链κ或λ，因此我们设计了针对Igκ的第二代CAR，IGK CAR。该构建体表现出高靶标特异性，但在血清 IgG 存在的情况下表现出功效降低。由于 CD19 CAR 对血清 IgG 不敏感，我们设计了各种组合 CAR 构建体，以保持 CD19 CAR T 细胞功效，但具有 IGK CAR 靶标选择性。 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的靶标特异性，并且对sIgG的存在具有抵抗力。我们的结果表明，组合 CAR 方法可以提高目标选择性和功效。