KY1043, a novel CD25-directed PD-L1 IL-2 immunocytokine, delivers potent anti-tumor activity in vivo via an expansion of a Tcf1hi PD-1+ CD8+ T cell population
Miha Kosmac1, Timothy I Malcolm1, Joanne Shelton1, Hannah L Craig1, Dirk Zahn1, Krzysztof B Wicher1, Stephen D Gillies2, Cassie H Van Krinks1, Matthew M McCourt1
1Kymab Ltd., Cambridgeshire, United Kingdom
2Provenance Biopharmaceuticals Corp., Waltham, MA, United States
IL-2 therapy has been approved for cancer patients for 30 years, but its use has been limited due to tolerability issues. In this work we investigated the in vivo efficacy and mode of action of KY1043, a neutralizing anti-PD-L1 antibody fused via its light chains to an attenuated IL-2 with highly selective binding to the trimeric ‘αβγ’ IL-2 receptor (IL-2R) in human PD-L1 ‘knock-in’ (hPD-L1 KI) mice implanted with hPD-L1 KI MC38 colon carcinoma cells. We hypothesized that the KY1043 immunocytokine could induce effective tumor control, while minimizing the expansion of peripheral T cells and NK cells, which mediate systemic toxicity. Treatment with KY1043 at 10 mg/kg generated a potent anti-tumor response, with 75% of tumors cured after a single dose, and 100% following two doses, with no significant adverse effects. Furthermore, the therapeutic effect of KY1043 was superior to that of an anti-PD-L1 antibody co-administered with recombinant IL-2, at equivalent doses. Additionally, immunological memory was demonstrated, as treated mice were resistant to re-challenge with MC38 but not to other tumors. Analysis of the tumor microenvironment showed that KY1043 induced a significant increase in effector CD8+ T cells, with a particularly significant expansion of a less differentiated self-renewing CD8+ T cell population marked by Tcf1 and PD-1 expression. These Tcf1hi PD-1+ lymphocytes have been associated with successful responses to immunotherapy, likely due to their ‘stem cell-like’ properties and high proliferative capacity that in the right circumstances can give rise to tumor clearing effector cells. By contrast, analysis of the peripheral lymphoid organs such as the spleen showed an expansion of CD25+ FoxP3+ T Regulatory cells, mainly at the expense of fewer splenic B cells and T follicular helper cells, an effect which likely contributes to the favorable safety profile of the molecule. In conclusion, KY1043 induces highly effective tumor killing in vivo, believed to be driven by the preferential expansion of a recently discovered ‘stem-like’ CD8+ T cell population in the tumor microenvironment. These results challenge the dogma that selective binding to the dimeric ‘βγ’ IL-2R is required for tumor control and demonstrate that a CD25-directed immunocytokine may provide an advantageous therapeutic-index for the treatment of cancer.

Session: Therapeutic Antibodies 3 (Virtual Poster Session)
Category: IMMUNOLOGY: Preclinical and Clinical