A novel dual mechanism-of-action bispecific PD-1-IL-2v armed by a "βγ-only" interleukin-2 variant.

Introduction: Interleukin-2 (IL-2) is one of the first cytokines to be discovered as an immune agonist for cancer immunotherapy. Biased IL-2 variants had been discovered to eliminate Treg activation or enhance the tumor specific T cell cytotoxicity. However, all the biased IL-2 variants pose the risk to overstimulate immune response at a low-dose range. Here, we introduce a novel dual-MOA bispecific PD-1-IL-2v molecule with great anti-tumor efficacy in a high dosed manner.
Methods: The novel IL-2 variant was designed by structural truncation and shuffling. The single armed bispecific PD-1-IL-2v molecule and IL-2v were studied by immune cell activations in vitro and in vivo and anti-tumor efficacy in mouse model.
Results and Discussion: The IL-2 variant in this bispecific antibody only binds to IL-2Rβγ complex in a fast-on/off manner without α, β or γ single receptor binding. This IL-2v mildly activates T and NK cells without over stimulation, meanwhile it diminishes Treg activation compared to the wild type IL-2. This unique bispecific molecule with "βγ-only" IL-2v can not only "in-cis" stimulate and expand CD8 T and NK cells moderately without Treg activation, but also block the PD-1/L1 interaction at a similar dose range with monoclonal antibody.
Competing Interests: Authors LZ, YJ, CC, YL, RW, CF, LC, and SC were employed by the company Cure Genetics Co., LTD. Part of the results presented in the paper were in the PCT patent with the filing number of PCT/CN2023/070898 and untitled “NOVEL INTERLEUKIN-2 POLYPEPTIDES” and the authors LZ, YJ, YL, and RW are co-inventors. The authors declare that this study received funding from Cure Genetics Co., LTD. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
(Copyright © 2024 Jiang, Chen, Liu, Wang, Feng, Cai, Chang and Zhao.)