A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

10 min read
December 12, 2023

S Iadonato et al. Front Immunol. 2023 Dec

Therapeutic antibodies targeting tumor-infiltrating T cells through immune checkpoints (such as compounds specific to the PD-1/PD-L1 axis) have proved quite efficient in immuno-oncology. In addition to PD-1 and CTLA-4, VISTA is a target of interest, as it is also a checkpoint inhibitor of T-cell response expressed by infiltrating immune cells in the immunosuppressive tumor microenvironment (TME).

A novel study describes the selection of anovel anti-VISTA antibody, with no cross-reactivity toward murine VISTA, using genOway’s hVISTA preclinical mouse model. hVISTA mice were used to test compounds’ pharmacokinetic (PK) profile and capability to induce tumor growth inhibition (TGI), and to select the best candidate for further preclinica lstudies.

Selection of the best anti-VISTA antibody candidate based on its extended half-life (PK study)

Different anti-VISTA candidate antibodies were selected based on their clearance/half-life upon i.p. injection in hVISTA mice. A lead candidate (KVA12.1) was identified, as it displayed the longest serum half-life relative to other candidates (Figure 1). KVA12.1 exhibited a seven-fold longer half-life than VSTB174 (Janssen therapeutics previously used in human clinical trials).

Figure 1: Pharmacokinetic profile of candidate mAbs (KVA) compared with VSTB174 in plasma of hVISTA mice upon i.p.administration.

Treatment of hVISTA mice with different doses of KVA12.1 revealed a non-linear pharmacokinetics, suggesting a significant KVA12.1 clearance through target-mediated drug disposition (TMDD) at lower concentrations while target saturation occurs at higher doses. The KVA12.1 lead antibody was then engineered to further extend its serum half-life. The resulting KVA12123 antibody efficacy was then assessed in vitro and in vivo.

Novel anti-VISTA antibody, KVA12123, is able to modulate immune response ex vivo

KVA12123 specifically inhibits binding of VISTA with its partners and restores T-cell proliferation and function (IFNγ and TNFα secretion; Figure 2), demonstrating KVA12123 efficacy ex vivo.

Figure 2: KVA12123 reduces MDSC-mediated T-cell suppression. Monocytes were differentiated into MDSCs (myeloid-derived suppressor cells) for seven days using GM-CSF and IL-6 and then co-cultured with autologous PBMCs. An anti-CD3 antibody was added to the PBMC fraction to activate T cells along with an isotype control antibody or KVA12123.

Efficient tumor growth inhibition of KVA12123 anti-VISTA alone, or in combination with anti-PD-1 in vivo

hVISTA mice were engrafted with tumor cell lines considered as either immunologically “hot” (E.G7-OVA) or “cold” (MC38, MB49). An efficient inhibition of the tumor growth was observed upon treatment with the anti-VISTA as a single agent (42% TGI). When combined with anti-PD-1, its efficacy increased up to 70% TGI (Figure 3).

Figure 3: Anti-VISTA alone, or in combinationwith anti-PD-1, suppressed MC38 tumor growth in hVISTA mice.

TGI was associated with changes to the immune composition of the tumor microenvironment (Figure 4), leading to a decrease of immunosuppressive granulocytic MDSCs (G-MDSC), and an increase of anti-tumoral M1-like macrophages, cDC, NK and CD4+ T cells.

Figure 4: Percentages of tumor-infiltrating cells were analyzed using hVISTA mice treated with 20 mg/kg KVA12123 or hIgG1. Immune flow analysis of extracted MB49 tumors on day 12 (24 hours after the 3rd dose) is shown. Data are shown as means ± SD (n=8). P-value was obtained by unpaired t-test. *P<0.05, **P<0.01, ***P<0.001.

Finally, the authors showed that the KVA12123 anti-VISTA antibody is also a potent immuno modulator in “cold” tumors, generally considered as unresponsive to existing checkpoint inhibitors. Based on this study, KVA12123’s efficacy is currently evaluated in a Phase 1/2 clinical trial in patients with advanced solid tumors, alone or in combination with anti-PD-1 pembrolizumab.

These results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors.

hVISTA humanized mice used in this study are available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

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