Most antibody-drug conjugates (ADCs) approved for the treatment of cancer contain protease-cleavable linkers. However, it remains unclear whether cleavable linkers can be processed outside the lysosomes. Here, we propose that recycling endosomes contributes to the processing of a bispecific METxMET ADC containing a VC-cleavable linker, and discuss the implications for the rational design of ADCs that recycle to the plasma membrane.

Deka Biosciences has developed a therapeutic platform (called Diakines) that couples complementary cytokines together via a tumor antigen targeting, human antibody derived, single-chain variable fragment scaffold. In addition, Deka has developed an assay that evaluates each patient's immune system's response to each Diakine. This precision patient-selection method enables Deka to treat each patient with the Diakine that their immune system is best suited to respond to. The lead molecule, DK2¹⁰ (EGFR), has for the first time uncoupled wild-type Interleukin-2 inflammatory toxicity from its potent anti-tumor function via coupling with nature's anti-inflammatory cytokine, Interleukin-10. DK2¹⁰ (EGFR) clinical trials have begun.

TL1A is a pro-inflammatory protein expressed on APCs, endothelial cells, and exists as a cytokine in serum. TL1A is induced in APCs by TLR ligands and Fc receptor cross-linking. TL1A signals through DR3, found primarily on T cells, NK, ILC, fibroblasts, and epithelial cells. MK-7240 binds both membrane-bound and sTL1A with high affinity and specificity and blocks DR3-mediated signaling. We characterise the mechanism-of-action of MK-7240 and show that sTL1A exists in human serum as both monomeric and trimeric forms and that MK-7240 binds to both forms, in addition to binding and blocking the membrane-bound form of TL1A.

In this study, we conducted a systematic comparison of eight different T-bsAb formats to understand how the molecular design of these antibodies affects their manufacturability and functionality. Our results showed that increasing scFv negatively impacted manufacturability, while functionality depended on various factors, including the format flexibility. Fab-FcK/scFv-FcH and Fab-FcK/FabscFv-FcH were identified as the optimal formats for developing Ig-like T-bsAbs.

CD3-engaging bispecific antibodies demonstrate strong anti-tumor activities in the clinic, but there is room to improve the efficacy and durability of these therapies. In this presentation, we will describe next-generation bispecific antibodies that engage T cell costimulatory pathways and discuss how they may be combined with CD3-engaging bispecifics to drive enhanced anti-tumor activity.

Success of bispecific antibodies (bsAbs) in solid tumors is still limited, amongst others due to insufficient accessibility of the tumor site and systemic toxicity that prevents effective dosing. B7-H3 (CD276) recently attracts considerable interest as target antigen in a variety of malignancies including GI cancers due to its rather tumor-specific expression on cancer cells and the microenvironment/vessels, the latter facilitating access of immune effector cells to the tumor site. Using our IgG-based proprietary antibody platform, we developed an optimized B7-H3xCD3 bsAb with improved efficacy and reduced toxicity after fine-tuning binding to both, B7-H3 and CD3. We envisage to initiate a first in human study with this bsAb, designated CC-3, in patients with metastasized colorectal cancer in Q3/2023, followed by a second trial including patients with various upper GI cancers. The implementation of these trials will benefit from already available favorable safety and efficacy data obtained in three single agent clinical trials with our PSMAxCD3 construct in the same bsAb format.

This presentation explores the evolving landscape of benefit-risk considerations for bispecific antibodies amid expanded indications and emerging technologies. It highlights the potential of bispecific antibodies in addressing complex biology in fields such as oncology, immunology, and rare disease. By delving into the latest research, this talk offers valuable insights into optimizing benefit-risk assessments and ensuring the successful discovery, development, and deployment of bispecific antibodies across diverse therapeutic areas.

The development of antibody drug conjugates (ADCs) for the treatment of acute myeloid leukemia (AML) has been limited by the availability of unique disease-specific antigens. Gemtuzumab ozogamicin (GO) is the only ADC approved for use in CD33+ AML patients, but is associated with dose-limiting toxicities. The use of bispecific antibodies represents a novel approach to the development of ADCs with the potential of a more efficacious and safer treatment option for patients in the future. Here, we describe the twin antigen validation and target cell selectivity of an aCD7/aCD33 bispecific ADC.

SAR443765 as a novel, anti-TSLP/anti-IL-13 Nanobody molecule significantly reduces FeNO, a biomarker of ongoing airway inflammation, in participants with asthma after a single dose. In addition, combined TSLP/IL-13 blockade improves lung function, particularly small airway dysfunction shown to correlate with poor disease control and type 2 inflammation. The effects surpass those reported for monovalent IL-13 or TSLP pathway targeting and suggest potential for superior effects in patients with asthma.

The presentation highlights how TAVO412, a trispecific anti-cMET x anti-EGFR x anti-VEGF antibody has strong preclinical activity in triple negative breast cancer, gastric cancer, pancreatic cancer, and small cell lung cancer.  A strategy of using combinations of standards of care treatments demonstrated stronger tumor growth inhibition. In addition, we highlight mechanisms of action of the engineering that contribute to solid tumor control.