Enhancing AML Therapy: The Impact of HMBD004, a Dual-Targeting Anti-CD47xCD33 Antibody

CD47 is recognized for its role as an inhibitory signal on normal cells, preventing their clearance by the immune system. However, its overexpression in tumors is linked to immune evasion and poor outcomes. Targeting the CD47-SIRPalpha interaction can boost the immune system's ability to attack cancer cells, but this approach faces challenges due to CD47's widespread presence, which can lead to reduced drug availability at the tumor site and potential off-target effects, notably with red blood cells.

CD33, on the other hand, is found on myeloid cells and is significantly overexpressed in the majority of AML cases, marking it as a potential therapeutic target. The effectiveness of CD33-targeted therapies has been demonstrated by drugs like gemtuzumab ozogamicin, although concerns regarding toxicity have led to its withdrawal from the market.

Hummingbird Bioscience has developed a novel therapeutic antibody against CD47 using a proprietary platform. Through computational methods, a highly specific epitope was identified, leading to the creation of a monoclonal antibody with high affinity and specificity. This antibody, 11a1, showed complete inhibition of SIRPalpha binding and induced effective phagocytosis of tumor cells in vitro.

Further development led to a bispecific antibody that targets both CD47 and CD33. This construct, HMBD004, retained the inhibitory properties of the original antibody while minimizing the risk of hemagglutination. It also displayed a preference for targeting CD47+ CD33+ cells and demonstrated significant tumor reduction and prolonged progression-free survival in mouse models of AML.

The research underscores the advantages of combining CD33 targeting with anti-CD47 therapy to enhance specificity, efficacy, and safety in treating AML. Hummingbird Bioscience is progressing HMBD004 towards clinical trials.