Pipeline | TBS-2025

TBS-2025: A first-in-class VISTA-inhibiting monoclonal antibody

VISTA is a novel checkpoint expressed on quiescent (resting) T cells and highly expressed on myeloid cells. While VISTA is expressed on a wide variety of solid tumor cancers, its role in resistance or failure of cancer- immunotherapy is not as well established in hematological malignancies. Emerging scientific evidence demonstrates that mutNPM1 and mutDNM3TA, two of the most common mutations in AML and other myeloid (blood related) malignancies, drive the expression of VISTA on leukemic blasts in AML and are reported to be the primary mechanism by which AML has a poor response to and high relapse rate following current therapies. VISTA expression is linked to high relapse rate in AML due to its ability to allow leukemic blasts to evade immune recognition and attack by the patient’s immune system. When VSIR, the gene that encodes for VISTA is silenced, an immune response is observed and survival is enhanced in murine models of mutNPM1 AML.

Development Background 

TBS-2025, a VISTA inhibiting antibody, was initially investigated by Kineta in a large Phase 1 trial either as monotherapy (n=24) or in combination with pembrolizumab (n=15) among patients with advanced, therapy refractory cancers, including, breast, lung, colorectal and ovarian cancer. The drug demonstrated a favorable safety profile at the highest dose level of 1,000mg administered every two weeks. No significant anti-tumor activity was observed among the 39 patients treated in the trial.

Recently, several new drugs called menin inhibitors have received accelerated approval in patients with relapsed and refractory mutNPM1. Menin is the “carrier” protein that exerts the proliferative effect on leukemic blasts. While the response rates of 25% to 30% that are seen following therapy with menin inhibitors are encouraging, they are short in duration followed by leukemia recurrence and subsequent short survival. We plan to investigate adding TBS-2025 in treatment of patients with mutNPM1 r/r AML who are receiving a menin inhibitor in a proof-of-concept study among 30 patients. If positive, this application of TBS-2025 would address an unmet medical need and may qualify for development under the FDA’s accelerated approval pathway.