We developed antibodies exquisitely selective to HER2 S310F/Y, two of the most common oncogenic mutations in the HER2 extracellular region. Cryo-EM structures reveal that these antibodies mimic the dimerization arm of HER and inhibit dimerization. As T cell engagers, they selectively killed a HER2 S310F-driven cancer cell line in vitro and in a mouse xenograft model. Overall, these antibodies appear to be promising candidates for clinical development.

Xencor has developed a robust bispecific antibody platform based on a novel set of Fc domain substitutions that promote high heterodimer yield and facile purification. We'll discuss application of this platform to the development of classic CD3 bispecific antibodies and CD28 costimulatory bispecifics. The XmAb 2+1 format—enabling bivalent targeting of a tumor-associated antigen and monovalent engagement of CD3—promotes higher tumor/normal selectivity with growing clinical validation. Moreover, the development of CD28 bispecific antibodies provides a new avenue for T cell activation, coupling with either CD3 bispecifics or PD1 blockade to promote stronger T cell response against tumors.

We have previously developed therapeutic immunocytokines (IC) which link interleukin-2 (IL-2) to anti-cytokine antibodies that bias IL-2 towards potentiating immune effector cells and promote tumor clearance. Here, we engineered a novel immunocytokine which replaces IL-2 with a variant that elicits memory-biased immune responses. The resulting molecule induces both effector cell responses for tumor elimination and memory responses to prevent cancer reoccurrence, representing a powerful new strategy for cancer treatment.

There is significant interest in utilizing single-domain antibodies (sdAb), as therapeutics, as their small size affords favorable properties such as increased tumor penetration and the ability to utilize prokaryotic production methods. Here, we demonstrate that rational swapping of surface-exposed cationic residues with anionic restudies, in combination with fusion to a homotrimeric peptide domain, significantly extends half-life and delays renal filtration of sdAb. Further, we combine these modifications with FcRn-binding peptide fusions to facilitate transmembrane transport in a mouse model. These rational modifications may improve the suitability of nanobodies for use as therapeutics, particularly in combination with alternative delivery systems.

We present a two-step sequential conjugation approach that marries the site specificity of the bacterial transglutaminase (TG) reaction with the robustness of Diels-Alder (DA) chemistry to generate stable antibody conjugates. In addition, we show strong potency of antibody conjugates, prepared via TG-DA chemistry, in both cell-based assays and a mouse model. Overall, our conjugation approach is site specific, versatile, and stable.

This presentation will focus on the convergence of a new high-throughput antibody discovery platform capable of screening 100s of millions of antibodies with machine learning to accelerate the full discovery process. This work is resulting in the identification of high-affinity, developable modalities fit for therapeutic use in accelerated time frames, while generating significant amounts of data and further refining our algorithms and models.

Accumulation of somatic hypermutation (SHM) is the primary mechanism to enhance the binding affinity of antibodies to antigens in vivo. Here, we built a high-throughput structural bioinformatics pipeline to study the effects of SHMs on antibody conformation, flexibility, stability, and affinity. Our study revealed a common mechanism of antibody conformation and stability modulation by framework mutations and epistatic effects between framework SHMs.

In recent years, engineering of pH-sensitive therapeutic antibodies has gained traction, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are costly and laborious, requiring repeated rounds of experiments under different pH conditions. Inexpensive computational techniques to predict the effectiveness of His pH-switches require antibody-antigen complex structures, which are often lacking. To circumvent these requirements, we introduce a sequence-based method for predicting His mutations in the variable region of antibodies, which could lead to pH-biased antigen binding called Sequence-based Identification of pH-sensitive Antibody Binding (SIpHAB).

By ablating all disease-associated functions of a given protein at once, targeted protein degradation has emerged as a promising therapeutic strategy to overcome limitations of traditional occupancy-based inhibitors To this end, at EpiBiologics, we are developing three fully recombinant and modular bispecific antibody-based platforms—AbTACs, KineTACs, & TrainTACs—that can be applied to effectively mediate degradation of cell-surface and extracellular proteins.

Spatially and temporally precise delivery of therapeutic macromolecules—such as bispecific T cell engagers—to tumors, while avoiding systemic toxicity, remains a challenge in transforming cancer treatment. OncoNano is developing the ON-BOARD ultra-pH sensitive micelle delivery platform to surmount these constraints. Herein, we report the efficacious masked delivery of a bispecific T cell engager to tumors in mice using ON-BOARD, demonstrating an improved safety profile and potential for clinical translation.

The clinical benefit of CTLA-4 blocking antibodies has been well established but treatment-related toxicities remain a limiting factor. XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding anti-CTLA-4 monoclonal antibody designed to maximize activity in the tumor microenvironment and improve tolerability compared with systemically active anti-CTLA-4 antibodies. This talk will cover design and preclinical characterization of XTX101, including demonstration of tumor regressions and tumor-specific pharmacodynamic changes in vivo.

GNAQ/11 mutations occur in up to 95% of uveal melanomas and are considered genetic drivers of the disease. PMEL17 (gp100) is a melanocytic lineage gene that is highly and broadly expressed in melanomas. DYP688 is a novel antibody-drug conjugate that binds to PMEL17 on target cells to deliver the payload SDZ475, a targeted inhibitor of Gq/11 oncogenic signaling. Preclinical and early clinical development of DYP688 will be discussed.