HPN217 Demonstrates Therapeutic Efficacy to Target BCMA for MM

A phase 1/2 clinical trial investigated HPN217, a tri-specific T Cell-Activating Construct (TriTAC) designed for B-cell maturation antigen (BCMA) therapeutics, serum albumin for half-life extension, and to CD3ε for redirecting T-cells against multiple myeloma (MM) cells. These data were presented at the 2021 ASH Annual Meeting.

“BCMA is a cell surface receptor highly and selectively expressed on normal and transformed plasma cells in patients with MM. We examined factors that may impact the therapeutic efficacy of HPN217, including the target BCMA in membrane-bound or soluble form, and concomitant or combination therapeutics such as γ-secretase inhibitor (GSI) and dexamethasone,” explained Patrick Ng, PhD, Harpoon Therapeutics, California, and co-researchers.

The researchers used a patient-derived 3D-culture system (3DTEB) to recapitulate biology within a bone marrow microenvironment and evaluate the effects of HPN217 against primary MM cells.

“3DTEBs were established from 5 patients with MM with varying ratios of autologous CD3+ T-cells to MM cells (0.15-0.6). Although the functional competence of the T-cells was unknown, HPN217 was able to mediate MM cell killing in 90% of the cultures with up to 71% of MM cells eliminated at a T-cell to MM cell ratio of 0.45,” continued Dr Ng and co-authors.

Flow cytometry showed the anti-tumor efficacy of HPN217 strongly correlated (R²=0.99) with BCMA expression on MM cells. This suggests the number of target receptors can be a limiting factor in efficacy.

Further, pre-incubation of target cells with 1 or 10 μg/mL anti-BCMA reduced the activity on HPN217 in T-cell dependent cellular cytotoxicity (TDCC) assays as shown by healthy donor T-cells and MM cell lines.

“There was no correlation between HPN217 activity and soluble BCMA in 3DTEBM. However, in TDCC assays, the addition of 6.25, 25 and 100 nM recombinant BCMA respectively led to 4-,9- and 28-fold increases in the EC₅₀ of HPN217. These data underscore the importance of preserving BCMA on MM cells and reducing soluble BCMA in circulation,” elaborated Dr Ng, and co-researchers.

Notably, the researchers conducted TDCC assays in the presence of 0.07-300 nM dexamethasone to simulate plasma concentrations relevant to dose levels of premedication for CRS. The highest dexamethasone concentrations caused ≤3-fold increases in the EC₅₀ of HPN217. This finding highlights the suppressive effect of dexamethasone on the anti-tumor activity of HPN217-redirected T-cells may be limited.

“We demonstrated HPN217 medicated BCMA-dependent primary MM cell killing by autologous T-cells, and that the density of BCMA target on the surface of MM cells and soluble BCMA affected the efficacy of HPN217 in cultures. GSI, which increased the expression of BCMA on MM cells, enhanced the efficacy of HPN217. On the other hand, dexamethasone had limited negative effects. HPN217 in combination with approved and experimental MM therapeutics is being evaluated in the 3DTEBM model,” concluded Dr Ng, et al.—Alexa Stoia

Ng P, Aaron W, Callihan E, et al. The Effects of BCMA Expression, Soluble BCMA, and Combination Therapeutics on the Anti-Tumor Activity of HPN217, a BCMA-Targeting Tri-Specific T Cell Engager Against Multiple Myeloma. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 1185.