A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

Abstract

The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

A pivotal decade for bispecific antibodies?

“…Finally, given the versatility of bsAbs and the potential to mediate completely novel MOAs, the field of bsAbs is poised to see novel emerging approaches and candidates enter the clinic, hopefully providing pivotal data in the years to come, both in oncology and in non-oncology indications, including applications in infection/virology, autoimmunity, metabolism, neurology and ophthalmology. These novel concepts include different approaches as described recently, 5 including the development of: 1) effector cell engagers different from TCEs, engaging, e.g., myeloid, NK or γδ-T cells, 96–98 2) in situ assembly concepts to specifically activate bsAbs on dual target-expressing cells 99 , 100 or in the tumor microenvironment, 101 3) PROTAC-like approaches resulting in internalization and degradation of membrane proteins, 102 4) antibody-based cytokine mimetics to trigger cytokine receptors, 103 , 104 and 5) unique solutions for delivery of bsAbs beyond barriers such as the blood-brain-barrier, 105 which may have applications for the treatment of neurodegenerative and other diseases. 106 …”

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

“…Successful agonism generally relies on both the proximity and orientation of paratopes with respect to one another and conformational sampling (i.e., the distribution of structural conformations of the molecule in solution). Some examples include IgG hinge modifications 23 , 28 , polymer-based Fab-Fab linkers 53 , tandem single and/or variable domain formats 24 , 25 , 38 , 54 , engineered single domain formats 39 , 55 , and complex constrained formats 21 . While these aforementioned strategies have demonstrated success in vitro and, in some cases, pre-clinically, many deviate significantly from the conventional IgG format that has become a proven therapeutic modality, thus adding molecule risk to an already high-risk therapeutic hypothesis with complex pharmacology.…”

Design and engineering of bispecific antibodies: insights and practical considerations

“…Agonistic bsAbs that activate two receptors on the surface of the same cell (cellular in-cis activation) can be used to selectively control signaling mechanisms by precisely steering bridging of receptor subunits. In one example, a bsAb targeting the interleukin (IL)-2 receptor subunits IL-2Rβ and IL-2Rγ was used to increase signaling through the intermediate affinity IL-2Rβγ while downregulating signaling through the high affinity IL-2Rαβγ ( Ha et al, 2021 ). In another example a dual agonistic bispecific Surrobody targeting death receptor (DR) 4 and 5 showed superior potency than combinations of the parental antibodies potentially due to heterodimeric clustering of DR4 and DR5 ( Milutinovic et al, 2016 ).…”