Abstract 1729: Integrative immune profiling of syngeneic tumor models provides predictive immune signatures for treatment response with HMBD002, a novel anti-VISTA neutralizing antibody
P477 HMBD-002-V4: A novel anti-VISTA antibody that uniquely binds murine and human VISTA and potently inhibits tumor growth by remodeling the immunosuppressive tumor microenvironment
Jerome Boyd-Kirkup, PhD, Dipti Thakkar, PhD, Vicente Sancenon, PhD, Siyu Guan, PhD, Konrad Paszkiewicz, PhD, Piers Ingram, PhD
Hummingbird Bioscience, South San Francisco, CA, USA
Correspondence: Piers Ingram (firstname.lastname@example.org)
Immune checkpoint therapies have shown unprecedented clinical activity in several types of cancer, however, less than 30% of patients respond. VISTA is a co-inhibitory immune checkpoint receptor of the B7 family and functions to suppress human T-cell activity. VISTA is highly expressed on tumor infiltrating myeloid cells including myeloid derived suppressive cells (MDSC), which have been associated with resistance to immunotherapy. Increases in VISTA+ cells have also been observed in response to PD1 and CTLA4 therapy. Targeting VISTA could represent a novel treatment axis in the non-responder population.Despite the promise of VISTA, limited structural information, lack of a definitive ligand, and incomplete data on expression in normal vs. disease contexts, have made development of drug candidates challenging. Further, previous anti-VISTA antibodies have only bound to rodent or human VISTA, making it impossible to translate pre-clinical efficacy and safety data to predict patient response.
HMBD-002-V4 is a humanized anti-VISTA antibody developed using Hummingbird Bioscience’s proprietary Rational Antibody Discovery platform to target a specific epitope predicted by structural modeling to block ligand binding and be conserved between human, cyno and murine VISTA.
In vitro, HMBD-002-V4 showed dose-dependent inhibition of the interaction between VISTA and the putative ligand VSIG3 for both human and mouse orthologs, and further demonstrated release of VISTA inhibition on T-cell activity and increased secretion of pro-inflammatory cytokines in human ex vivo assays.In vivo, HMBD-002-V4 showed single agent tumor growth inhibition (TGI) of up to 40% in syngeneic murine CDX models, however, efficacy was significantly improved if combined with anti-PD(L)1 antibody where TGI above 94% was possible. Profiling of representative tumors by FACS revealed MDSC infiltration in these models that was significantly increased after treatment with anti-PD(L)1 antibody and associated with an increase in immunosuppressive serum cytokines. Conversely, HMBD-002-V4 efficacy was associated with decreased MDSC infiltration for both monotherapy and combination arms and a remodeling of the tumor microenvironment towards a pro-inflammatory phenotype. In models without MDSC infiltration, HMBD-002-V4 showed poor efficacy. HMBD-002-V4 was evaluated for pharmacokinetics and toxicology and demonstrated excellent serum half-life of 11 days, with no observable toxicity in multiple animal models. Further, HMBD-002-V4 has been optimized for manufacturability, including high expression titers and stability.
HMBD-002-V4 represents a promising therapeutic candidate for the treatment of VISTA-mediated suppression of anti-tumor immunity. Predictive biomarkers of response to HMBD-002-V4 are currently being explored in multiple indications and the first-in-human trial of HMBD-002-V4 is planned for 2019.
The study was approved by the SingHealth Institutional Animal Care and Use Committee, approval number 2016/SHS/1230.