Main Conference Day 2 - Oct 23, 2024Wednesday, 23 October 2024 - JT (Japan Time, GMT+09:00)

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. PDAC organoid screening identified a novel payload of antibody–drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We selected CEACAM6 as an ADC target. The Anti CEACAM6-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells. Combination with PD-1 antibody induces more sustained tumor regression.

Payload resistance is a critical concern for ADCs: patients progress, narrow payload diversity, and limited validation of novel modes-of-action. Combining ADCs with other drugs may be beneficial but therapeutic windows are limited. Hummingbird Bioscience's dual-payload ADC platform presents a targeted, single-agent approach designed to overcome resistance and maximize therapeutic window.

Eisai has been tackling development of therapies for Alzheimer’s disease (AD) for over 4 decades. Eisai had spent a long time with a lot of development failures of disease modifying therapies for AD, but we had never given up and then eventually developed anti-Ab protofibril antibody, Lecanemab, in 2023.

Acasunlimab, a novel bi-specific antibody generated with DuoBody platform, targeting PD-L1 and 4-1BB, enhances T cell anti-tumor activity by blocking PD-L1 and inducing conditional activation of 4-1BB signaling. In preclinical studies, it effectively binds to its targets, enhances activation and proliferation of TCR-stimulated T cells and induces tumor regression without causing systemic toxicity. In a phase I/IIa study, Acasunlimab showed promising safety and efficacy profiles across various tumor types and further study is currently ongoing. We will present an overview of Acasunlimab development with key pre-clinical and clinical data.

We have been conducting research on radio-theranostics with our proprietary platform technology.　The most advanced pipeline, NMT25, is an Ac-225 labeled humanized antibody against MUC5AC, which is highly expressed in pancreatic cancer.　NMT25 has demonstrated good pharmacokinetics and excellent antitumor efficacy in animal models. A Phase I study of the diagnostic agent NMK89, a theranostic pair of NMT25, is currently under way. In this presentation, we introduce our efforts in radio-theranostics development, focusing on NMT25/NMK89.

Quick feedback on what people designed and produced and how they exist in their hands is essential for developing novel molecules and formats, but it isn't easy to happen. Rigaku developed a 'solution molecular microscope' that can image the molecular complexes in a solution that enables direct epitope mapping, molecular defects and aging, and nucleotide/protein quantitation of vector complexes.

Multispecific antibodies are widely used in Immunooncology. We expand their use also to Inflammation with learning from the past and translating knowledge of multispecific antibody design from oncology to inflammation. Important design principles are shared and the advantages of Numab's platform presented. The audience will be updated with pre-clinical and clinical data.

There is increasing understanding that currently approved monospecific checkpoint inhibitors are not sufficiently effective for all patients and/or indications. Thus, investigators are interested in targeting multiple signaling pathways and/or cell types to enhance the depth and breadth of clinical outcomes, often in the form of multispecific antibody treatments (‘multispecifics’). The large number of possible topologies and complexity of manufacturing of multispecifics necessitates the development and application of a robust set of complementary technologies. We have developed an exemplary set of such technologies, and herein, demonstrate the ability to direct desired antibody chain pairing (HC-HC and HC-LC), isolate and engineer single-domain antibodies, as well as generate large panels of multispecific antibodies with diverse topologies from a limited number of input molecules. Specifically, we demonstrate these capabilities in the context of T cell engaging (TCE) multispecifics that leverage our affinity- and developability-optimized aCD3 and aCD28 antibody panels.

Recurrent genital herpes are mostly caused by Herpes simplex virus-2 and no effective treatment is currently available. We engineered dual-action neutralizing antibodies blocking viral entry and cell-to-cell spread. Promising results in reducing viral shedding and lesions in vivo suggest a transformative approach for chronic suppressive therapy.

Bispecific antibodies are a rapidly growing and clinically validated class of antibodies with marketed drugs. We have designed a novel tetravalent symmetrical bispecific antibody format called REGULGENT^TM, which utilizes four Fab domains with a common light chain. REGULGENT^TM demonstrates an ideal profile for commercial use by avoiding the formation of unintended molecules, resulting in high expression levels. We further show the product applications using this format.

Many cancers are driven by hyperactive mutants of intracellular proteins, most of which remain undruggable by the conventional approach with small molecule drugs. I will discuss biologics-based strategies to effectively target intracellular cancer drivers, including facile development of monobodies that are exquisitely selective to oncogenic mutants over their wild-type counterparts, and intracellular delivery of such monobodies.

In this presentation, I will describe the development of a D-monobody against MCP-1 using mirror image display. The obtained D-monobody showed efficient inhibition of MCP-1 activity (IC50 = 2 nM). I will also present a monobody and anticalins targeting small molecule ligands for bio-analytical applications.

Establishment of a technological platform for the creation of cell-permeable peptides enabling targeting of intracellular proteins could be a major step toward developing innovative drugs. We have discovered the drug-likeness criteria for cyclic peptides and established a new peptide drug discovery platform by developing library technologies affording highly N-alkylated cyclic peptide hits. As an example of its utilization, the discovery of a RAS inhibitory clinical compound (LUNA18) will be reported.