Harnessing Innate Immunity: The Development and Efficacy of CTX-8573 in Multiple Myeloma Therapy

The abstract introduces CTX-8573, a novel multispecific antibody designed to target the B-cell maturation antigen (BCMA) found on multiple myeloma (MM) tumor cells, with the aim of enhancing the cytotoxicity of natural killer (NK) and γδ T cells. This approach is considered due to the limitations of current MM treatments and the potential of innate immune system-based therapies.

The method involved creating bispecific constructs that link anti-NKp30 Fab fragments to an anti-BCMA IgG1 antibody, which has an afucosylated Fc region to improve binding with CD16a. Variants with an aglycosylated Fc were also produced to study the effect of NKp30 engagement alone. In vitro assays were conducted using primary NK and γδ T cells to evaluate activation, cytokine production, proliferation, and cytotoxicity against tumor cells with varying BCMA levels. In vivo studies were carried out in humanized mouse models, and pharmacokinetics and safety were assessed in Cynomolgus monkeys.

Results showed that CTX-8573 is stable and binds BCMA and NKp30 effectively. It induces potent cytotoxicity in BCMA-expressing target cells with an EC50 significantly lower than that of BCMA monoclonal antibodies. Notably, CTX-8573 is also effective against low BCMA-expressing cell lines. The aglycosylated variant indicates that NKp30 engagement is sufficient for innate cell activation, though CD16A binding further enhances this activity. CTX-8573 maintains its cytotoxic activity even in the presence of soluble BCMA or its ligands, and does not cause NK-cell fratricide. In humanized mouse models, it exhibits anti-tumor efficacy, and in monkeys, it shows standard pharmacokinetics without systemic immune activation.

The conclusion emphasizes CTX-8573 as a promising bispecific antibody that can significantly enhance NK and γδ T-cell-mediated tumor killing. It has demonstrated strong anti-tumor efficacy in vitro and in vivo, a broad therapeutic window, and no systemic toxicity, along with favorable pharmacokinetics and manufacturability. This suggests that CTX-8573 could be a valuable addition to MM treatment strategies.

The disclosures reveal affiliations and potential conflicts of interest involving Compass Therapeutics LLC and the University of Louisiana at Lafayette for the individuals named in the document.