Tumors use sugars, or glycans, to evade the immune system. I will describe development of antibody-lectin bispecifics as a modular and programmable approach to target glycans for cancer immunotherapy.

PROteolysis TArgeteing Bispecifcs (PROTABs) are antibodies that colocalize transmembrane E3 ubiquitin ligases with target receptors to induce their ubiquitination and degradation. We will describe the discovery of PROTABs targeting ligases overexpressed in colorectal cancer and their activities in vitro and in vivo. We further demonstrate applicability of PROTABs for multiple ligases and receptors and describe protein engineering rules for maximizing the efficiency of degradation.

At Synthekine, we have generated a series of functional synthetic cytokine agonists (SCAs) that mimic and modulate natural signals or create new ones. These molecules are expected to provide therapeutic immunomodulation while exhibiting antibody-like druggability. 

This talk will describe a new generation of PD1-cis-targeted IL-2R agonists resulting from the fusion of a high-affinity PD-1 antibody to an IL-2Rbg agonist. Such agonists maintain the advantages of IL-2Rbg-biased agonists for systemic immunotherapy, but in addition allow the expansion of a unique subset of less exhausted and more cytotoxic effector T cells when acting on antigen-experienced stem-like CD8+ T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

T cell engagers are highly potent anti-cancer immunotherapeutic molecules. However, on-target, off-tumor toxicity and cytokine release syndrome (CRS) limit the broad application of these drug modalities. Through several case studies, we’ll showcase the development of next generation immune engagers that can better engage and modulate T cell reactivity with the aim to decouple tumor cell killing from systemic toxicity.

Biology focused design: AZD9592 is a first-in-class bispecific ADC designed to target EGFR and cMET, while overcoming pathway-mediated resistance mechanisms that limit other targeted agents. The ADC was constructed on the backbone of the DuetMab monovalent bispecific IgG platform and was engineered with higher affinity for cMET compared to EGFR (>15 fold), with the aim of reducing EGFR-driven toxicity in normal tissues. The antibody is conjugated via a cleavable linker to a topoisomerase 1 inhibitor (TOP1i) payload (AZ14170132). AZD9592 is broadly active in PDX models representing clinical line-of-sight and shows a promising safety profile.

• Review the multiple technologies have recently emerged to induce targeted degradation of cell surface or secreted proteins including LyTACs, PROTAbs/AbTACs, and KineTACs
• Discuss pros and cons of targeted degradation vs. inhibition, and where targeted degradation may be most applicable
• Compare different antibody-mediated degradation technologies and discuss where they may be optimally used
• Discuss what protein-engineering approaches might be applicable to enhance degradation efficiency

Xencor is developing a growing pipeline of CD3 and CD28 T cell engagers, together with several potency-optimized cytokine-Fc fusions, including IL15, IL12, and IL18. We will discuss preclinical data exploring combination of these various agents with themselves and PD1 inhibition to promote optimal T cell activation in the tumor microenvironment.

This presentation will describe key pre-clinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell targeted enhancement strategies in pre-clinical development will be discussed.

Antibodies CD28 bispecific antibodies (bsAbs) were generated to co-stimulate T cells in the presence expressing a selected tumor-associated antigen (TAA) or by co-engaging PD-L1 on cancer cells or antigen-presenting cells. Using our κλ body antibody platform, CD28 bsAbs targeting multiple TAAs were designed for tumor-specific activation of the immune system. CD28-engaging κλ bodies enhance the antitumor response via stimulation of T cell proliferation and activation, increased cytokine secretion, and directed cytotoxicity. Desired characteristics of the anti-CD28 arm, approaches to drive selective co-engagement, and TAA-dependent co-stimulation versus immune checkpoint-dependent co-stimulation will be discussed.

The presentation will cover an overview and update on preclinical properties of solid and heme tumor co-stimulators including FAP-4-1BBL, CD19-4-1BBL, and CD19-CD28 in active clinical development in combination with cibisatamab and glofitamab, respectively.

Duobody GEN1042 is a conditional activator of co-stimulatory molecules 4-1BB and CD40 which has shown early promise in the treatment of advanced solid tumors. Preclinical data shows enhanced priming and anti-tumor activity inclusive of T cell proliferation and effector functions. Furthermore, monotherapy and combination data from our FIH, open-label, phase I/II trial (NCT04083599) reveal a manageable safety profile, clinical activity, and pharmacodynamics consistent with the mechanism of action.