Targeting Multiple Myeloma with CD38-Specific Bifunctional Immunotherapies: In Vitro and Ex Vivo Efficacy

Antibody recruiting molecules (ARMs) are innovative immunotherapies with a dual-acting structure, consisting of a target-binding component and a universal antibody binding terminus (uABT). The uABT recruits IgG antibodies to "opsonize" cancer cells, leading to their destruction by immune effector cells through antibody-dependent mechanisms.

Kleo Pharmaceuticals has created CD38-ARM molecules that target CD38, a protein highly present on multiple myeloma cells. Unlike existing treatments like Daratumumab, CD38-ARMs facilitate antibody-dependent cellular cytotoxicity (ADCC) without depleting immune effector cells that express CD38.

The CD38-ARM molecules were developed using a cell-free peptide discovery system, identifying cyclized peptides with selective binding to human CD38. These were then linked to the uABT to form the final molecules. The binding and activity of CD38-ARM were assessed through various assays, including ternary complex formation, surrogate CD16a binding and signaling, and live cell imaging.

In tests, CD38-ARM demonstrated high affinity for CD38 and human IgG1/IgG2. The compounds showed activity in assays, with KP-6 and KP-7 exhibiting potent EC50 values in NFAT activation and ADCC assays, comparable to Daratumumab. Importantly, CD38-ARM did not cause depletion of NK cells, unlike Daratumumab.

Ex vivo tests using bone marrow samples from multiple myeloma patients showed that CD38-ARM could significantly reduce myeloma cells at certain concentrations, similar to Daratumumab, while preserving normal CD38+ immune cells.

The study concludes that CD38-ARMs have therapeutic potential, offering a novel approach to killing multiple myeloma cells via ADCC without depleting immune cells and without complement activation, which may reduce infusion reactions. This represents a significant advancement in the ARM platform's ability to create targeted therapeutic agents.

Disclosures indicate that several individuals associated with the study are employed by Kleo Pharmaceuticals or Peptidream Inc., and some hold equity ownership in Kleo Pharmaceuticals.