Unlocking the Potential of HPN217: Targeting BCMA for Innovative Multiple Myeloma Therapy

In 2018, the US saw an estimated 31,000 new multiple myeloma (MM) diagnoses, with nearly 13,000 fatalities due to this incurable condition. While traditional chemotherapy and various targeted therapies, such as proteasome inhibitors, HDAC inhibitors, and antibodies, have been employed, there is a need for innovative treatment options. One such approach involves targeting the B cell maturation antigen (BCMA), which has shown promise in CAR-T therapies and antibody-drug conjugates for relapsed refractory MM (RRMM).

A novel treatment, HPN217, is a tri-specific T cell activating construct (TriTAC) that includes binding domains for human BCMA, human serum albumin (HSA), and the T cell receptor (TCR) complex. This construct is a stable single polypeptide with a molecular weight of approximately 53 kDa, produced by CHO cells. The simultaneous binding of BCMA on MM cells and CD3 on T cells triggers T cell activation and the destruction of target MM cells.

The inclusion of an HSA binding domain in HPN217 is a unique strategy that extends the serum half-life of the molecule and provides it with a small size and flexibility, distinguishing it from other CD3-based bispecific T cell engaging molecules that use Fc-engineering.

The binding affinities of HPN217 for recombinant human BCMA, HSA, and CD3ε were determined to be 5.5 nM, 6 nM, and 17 nM, respectively, using biolayer interferometry. Flow cytometry confirmed the construct's binding to native targets on the cell surface. In vitro pharmacological activity was evaluated using T cell-dependent cellular cytotoxicity (TDCC) assays, demonstrating dose-dependent and BCMA-dependent cytotoxicity with EC50 values ranging from 0.05 to 0.7 nM.

The in vivo properties of HPN217 were assessed in xenograft models and a pharmacokinetic study in cynomolgus monkeys. The construct showed dose-dependent growth suppression against certain MM and lymphoma models with low BCMA expression levels. In the pharmacokinetic study, HPN217 displayed linear behavior and a serum half-life of 64 to 85 hours, with stability and intactness maintained up to 3 weeks in vivo.

The preclinical and nonclinical data indicate that HPN217 is an effective therapeutic candidate with the potential for a convenient dosing schedule. A phase 1 clinical trial is planned to assess the safety and efficacy of HPN217 in patients with RRMM.