Harnessing Innate Immunity: The Potential of CTX-8573 in Multiple Myeloma Therapy

The text discusses a new approach to treating multiple myeloma (MM), a disease for which current treatments have improved survival but not cured the condition due to eventual relapses. The focus is on enhancing the innate immune system's role in therapy, as it has been less explored compared to the adaptive immune system. The paper introduces CTX-8573, a multispecific antibody designed to target the B-cell maturation antigen (BCMA) found on tumor cells and to activate natural killer (NK) and γδ T cells via the receptors NKp30 and CD16a.

The methodology involved creating bi-specific constructs that combine an anti-BCMA antibody with anti-NKp30 fragments. Variants were also made to test the effect of targeting NKp30 without the involvement of CD16a. In vitro testing was conducted to evaluate the activation of innate cells, cytokine release, proliferation, and cytotoxicity against tumor cells with varying BCMA expression. In vivo studies were carried out using humanized mouse models, and the drug's pharmacokinetics and safety were assessed in Cynomolgus monkeys.

Results showed that CTX-8573 is stable and binds effectively to BCMA and NKp30. It significantly enhances the cytotoxicity of NK and γδ T cells against BCMA-expressing tumor cells, with a much lower effective concentration needed compared to standard BCMA antibodies. The drug is effective even against cells with low BCMA expression, where other antibodies are ineffective. The variant lacking CD16a binding still exhibits cell-killing activity, indicating that NKp30 engagement alone is sufficient for innate cell activation. However, the presence of CD16a enhances the effect.

CTX-8573 maintains its cytotoxic activity regardless of the presence of soluble BCMA or its ligands, APRIL and BAFF. Importantly, it does not trigger unwanted innate cell activation or cytokine production in the absence of BCMA-expressing target cells, which suggests a broad therapeutic margin. Unlike another drug, daratumumab, CTX-8573 does not cause NK-cell fratricide. In vivo, the drug demonstrates anti-tumor efficacy and, in monkeys, it shows typical pharmacokinetics with a long half-life and no systemic immune activation.

The study concludes that CTX-8573 is a promising new bispecific antibody that can significantly enhance the killing of tumor cells by NK and γδ T cells. It shows strong anti-tumor effects both in vitro and in vivo, a wide therapeutic window without systemic toxicity, and favorable pharmacokinetics and manufacturability. This suggests that CTX-8573 could be a new treatment option for MM, either on its own or in combination with current therapies.