Antibody Drug Conjugates with a Novel Translation Inhibitor Payload Demonstrate Cytotoxicity and Tumor Growth Reduction in Multiple Myeloma Models

Background

Antibody drug conjugates (ADCs) are a validated modality for the targeted delivery of cytotoxic payloads to myeloma cells while sparing healthy tissue. To achieve the full potential of ADCs in multiple myeloma patients, it will be important to have ADCs that incorporate payloads with non-overlapping mechanisms of action (MOA) as compared to existing therapies. By mining a proprietary collection of small molecule natural products (NPs), Hexagon Bio has identified a novel protein translation inhibitor, HB-06510, which exhibits favorable physicochemical properties and significant sensitivity in myeloma cell lines. HB-06510 has been conjugated to antibodies that bind myeloma antigens and has been shown to induce myeloma cell cytotoxicity in vitro and in vivo.

Methods and Results

Hexagon Bio has established a platform to identify new NPs and determine their MOA. This platform uses a proprietary algorithm integrated with machine learning, genetic screening, and synthetic biology to identify, produce, and define the MOAs of new NPs, primarily isolated from our fungal library comprising > 100,000 strains. Using this platform, we identified a NP that was potently cytotoxic across a panel of cancer cell lines, including multiple myeloma (≤ 3.2 nM average EC50 and 100% killing across 10 cell lines in a 72 hour assay). To determine the mechanism of action, we used genetic screening and found that this NP inhibited protein translation. Physicochemical evaluation of the NP revealed it had good properties for a potential ADC payload (good solubility, low lipophilicity, good stability in human plasma and lysosomal preparations, no reactivity with glutathione), it has a site for linker attachment and is amenable to semi-synthesis and medicinal chemistry. Further cytotoxicity profiling demonstrated that HB-06510 is cytotoxic to multi-drug resistant cells, including those expressing high levels of efflux pumps such as Pgp and ABCG2, indicating that HB-06510 is not a substrate for these pumps. We also demonstrated that HB-06510 is cytotoxic to both fast- and slow-cycling cells and induces immunogenic cell death.

To evaluate the potential for HB-06510 to be an ADC payload, we conjugated HB-06510 to antibodies that bind myeloma antigens BCMA, CS1 and CD38 and have demonstrated anti-myeloma cell cytotoxicity in vitro and in vivo. These results will be presented.

Conclusions

We have identified a novel protein translation inhibitor payload that is highly potent, has good drug-like properties and shows effective anti-myeloma cell activity in vitro and in vivo when conjugated to anti-myeloma antibodies. ADCs with this MOA are distinct from both currently-available targeted therapeutics and chemotherapy and have the potential to provide benefit to patients.

No relevant conflicts of interest to declare.