This talk will explore the biology of toll-like receptors in cancer, review preclinical studies and mechanism of action and activity of ISACs, and share an update from the global phase I/II first-in-human trial using BDC-1001 in patients advanced HER2-expressing solid tumors.

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Novel therapies engaging both innate and adaptive immune response may produce robust and durable anti-cancer immunity. Activation of toll-like receptor 9 (TLR9) by unmethylated CpG oligonucleotides (ODNs) promotes innate inflammatory responses and the induction of adaptive immunity. Several CpG-ODNs have demonstrated clinical response in melanoma patients by intra-tumoral injection. We developed a novel toll-like receptor agonist antibody conjugate (TRAAC) platform to deliver a potent TLR9 agonist (T-CpG) for targeted immune activation via systemic administration. TRAAC molecules demonstrated robust immune modulation and potent single agent anti-tumor activity in preclinical settings, suggesting therapeutic potential across multiple solid tumor malignancies. 

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The signaling pathway comprising the hormone Relaxin-H2 with its GPCR RXFP1 has been implicated in a number of malignancies. Here we describe a novel antibody-targeted, siRNA-carrying lipid nanoparticles, where the siRNA knocks down the expression of RXFP1. Upon delivery to human ovarian cancer cells, the treatment retards cell growth in vitro and in a xenograft mouse model.

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The promise of oligonucleotide therapeutics is to use Watson-Crick-Franklin base-pairing rules to design drugs rationally based on genomic information. That promise has remained elusive because of cell barriers to oligonucleotide uptake. Receptor-mediated uptake through bioconjugation oligonucleotides has changed that. Avidity’s AOC technology uses monoclonal antibodies to cell surface proteins that are internalized to facilitate the functional delivery of oligonucleotide therapeutics into a broad range of cell and tissue types.

Leveraging the natural immune repertoire for antibody discovery has distinct advantages for positive downstream outcomes, including efficacy, developability and safety; however, traditional antibody capture and screening methodologies typically fail to provide both the throughput and resolution required to thoroughly mine the full genetic diversity. The addition of the Berkeley Lights Beacon platform to the Abveris antibody discovery workflow has greatly enhanced the development process for therapeutic drug discovery, enabling the identification of functional, high affinity, species cross-reactive antibodies for rapid clinical advancement. 

High dose IL-2 induces complete responses in certain cancers. Its use is limited due to toxicities. To specifically stimulate antigen-activated CD25+ effector T cells and avoid systemic NK and naïve T cell activation, we have developed a pegylated, CD25/CD122-selective IL-2 mutein (STK-012). STK-012 avoids IL-2 mediated toxicity and may enable the specific expansion of antigen activated memory T cells in cancer patients leading to durable tumor response.

Cytokines are potent immune modulators. However, systemic administration of cytokines for therapeutic purposes can result in pleotropic effects, with heterogenous activity across different cell types, ultimately limiting efficacy. We are pioneering a new approach with our cis-targeted cytokine therapies to activate only the immune cell types that drive desired responses. Our cis-targeted immunotherapies offer a new level of selectivity, with optimized efficacy and minimized toxicity.

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Traditional hybridoma and phage display methods have shown limited success in delivering therapeutic antibodies against difficult targets like most GPCRs and ion channels. Amelie Kutschera will present case studies of how Genovac has overcome this challenge by leveraging their core genetic immunization technology and Berkeley Lights’ Beacon OptoFluidic system to rapidly discover antibodies against challenging targets, focusing on GPCRs, from a variety of different animal species.  

Death receptor 5 (DR5) naturally binds ligand TRAIL, inducing receptor trimerization and activation of apoptotic pathways in a broad range of cancers. Agonistic anti-DR5 IgG antibodies have been unsuccessful in clinical trials due to insufficient DR5 multimerization to induce apoptosis. We developed multivalent IgM antibody, IGM-8444, to efficiently cluster DR5 and induce potent cancer cell killing while maintaining a good preclinical safety profile. A Phase 1 clinical trial is currently ongoing.

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Glycan-mediated immune regulation plays an integral role in immune activation and tolerance and is often dysregulated in cancer and autoimmunity diseases. However, due to the promiscuity and redundancy of glycan-receptor interactions and glycans’ structural heterogeneity, therapeutic intervention of this axis is challenging with conventional therapeutic modalities. We developed a platform technology of enzymatic cell surface sialoglycan editing to enable drug development in glyco-immunology to treat cancer and inflammatory diseases.

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LILRB4, an immune inhibitory receptor expressed mostly on monocytes, has emerged as a compelling novel target for monocytic AML because LILRB4 signaling in leukemia cells mediates T cell suppression and tumor infiltration. IO-202 is an antagonist antibody to LILRB4, capable of activating T cells, inhibiting tumor growth, and blocking leukemia cell infiltration in preclinical studies. IO-202 is currently being evaluated in a phase 1 study in AML and CMML.

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