LAUSR

Multiple Myeloma (MM) is a rare and incurable hematological malignancy. Despite emerging treatments, there is still an unmet medical need for novel therapeutics to target the inherent and acquired drug resistance associated with MM. CA102L is a conjugate of hyaluronic acid and an anticancer drug designed to deliver its payload, Lenalidomide (Len), to MM cells via the CD44 receptor. Lenalidomide is used as a front-line therapy in MM; The CD44 receptor is highly expressed in MM and is associated with advanced clinical stages and poor survival. In addition to the enhancement of the therapeutic efficacy of Len, a reduction in off-target toxicity is suggested. The present study was designed to evaluate the efficacy of CA102L in MM and identify its potential mechanism of action. The antitumor efficacy of CA102L was tested (in vitro and in vivo) in two MM cancer models, IM-9 and NCI-H929. Protein expression was used to identify the potential targets of CA102L in MM. Both in in vitro and in vivo investigations, CA102L as a single agent displayed an improvement in potency in MM models. In CB-17 SCID mice bearing either IM-9 or NCI-H929 cells, tumor growth inhibition was significantly higher (P< 0.05) in the CA102L (25 mg/kg) treated group compared to that of Len (25 mg/kg). Further, CD31 and hematoxylineosin (H&E) staining of tumor sections from the IM-9 xenograft mice treated with CA102L resulted in greater antiangiogenic and antiproliferative effects compared to the other groups. Prolonged survival was also observed in CA102L monotherapy in H929 models relative to Len (56% vs 11%). Interestingly, in H929 cell viability studies, CA102L and Len at 400μM showed comparable cytotoxicity with a 60% cell growth inhibition, while superior activity was noted against IM-9-treatments (CA102L 60%, Len 20%). Western blot studies confirmed CRBN as the primary target of CA102L. In summary CA102L as a single agent, exhibited greater efficacy than Len in preclinical MM models, thus representing a promising potential therapeutic strategy for MM. Studies presently are ongoing to further evaluate CA102L’s preclinical profile to advance the candidate into the clinic. Citation Format: Eskouhie Tchaparian, Star Lin. Evaluation of the antitumor activity of ca102l, a hyaluronic acid and lenalidomide conjugate, in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2007.