Harnessing the Power of SGN-CD48A: A Pioneering Anti-CD48 ADC in Multiple Myeloma Therapy

Multiple myeloma (MM) is a plasma cell cancer without a cure, necessitating the development of new targeted therapies to enhance remission outcomes. This study introduces SGN-CD48A, an antibody-drug conjugate (ADC) that targets CD48, a protein found on the surface of malignant plasma cells in 90% of MM patients. CD48 plays a role in immune cell modulation and is a potential therapeutic target due to its broad expression in MM.

The ADC, SGN-CD48A, consists of a humanized anti-CD48 monoclonal antibody (mAb) linked to eight molecules of monomethylauristatin E (MMAE), a cytotoxic agent that disrupts microtubules. The conjugation utilizes a novel glucuronide-MMAE linker that is cleavable by β-glucuronidase and features a PEG side chain and self-stabilizing maleimide. This design results in a uniform drug-to-antibody ratio and improved pharmacokinetics and antitumor efficacy.

Upon binding to CD48, SGN-CD48A is internalized by myeloma cells, leading to the release of MMAE, which induces cell cycle arrest and apoptosis. The ADC showed significant cytotoxicity against a range of human MM cell lines with varying levels of CD48 expression, while sparing normal resting B, NK, and T lymphocytes.

In vivo testing in mouse xenograft models of MM demonstrated the potent antitumor activity of SGN-CD48A, with complete remissions achieved in a majority of the mice at specific doses. The study underscores the effectiveness of targeted MMAE delivery via CD48 binding and highlights the potential of SGN-CD48A as a novel therapeutic for MM.

The researchers involved in this study are affiliated with Seattle Genetics, Inc., and some own equity in the company.