Oxford Biotherapeutics developed a novel proteomics target discovery platform (OGAP) for identifying cancer unique proteins/isoforms, with minimal expression in normal/NAT tissues. Plasma membrane protein abundance is directly measured in patient cancer and normal tissues, circumventing inaccurate RNA based predictions. This approach has led to the development of a unique set of antibody-based drug programs including ADCs, IO agonists & bispecifics eg., 076 ADC targeting DEC205, 003R a novel checkpoint agonist.

T cells recognize intracellular targets presented by HLA to enable potent anti-tumor immune responses, and these targets can be leveraged to generate off-the-shelf therapeutics using T cell bispecific engagers to treat a broad patient population. We've developed 3T-TRACE to rapidly identify the antigens of orphan T cells from patient tumors and 3T-PRIME, a TCR mimetic platform to rapidly generate potent and specific binders for therapeutic development.

The CAR T cells based on our antibody targeting GPC3 are being tested for treating liver cancer in a NIH clinical trial. In the present talk, I will discuss our recent work on validation of GPC2 and GPC1 as new therapeutic targets in cancer and engineering of CAR T cells for treating neuroblastoma and pancreatic cancer. I will also describe our new strategies including nanobody technology to improve efficacy of CAR T cells.

Glypican 3 (GPC3) is an attractive immunotherapeutic target given its preferential expression in several solid cancers. In pre-clinical studies, co-expression of IL15 enhances the antitumor properties of GPC3-CAR T cells (15.GPC3-CAR T cells). I will discuss the results emerging from two first-in-human, Phase I studies evaluating 15.GPC3-CAR T cells focused on safety, expansions, and antitumor responses in adults and children.

cON-05 is a bispecific antibody comprising an arm binding to HSG (histamine-succinyl-glycine) and a Fab directed against oxMIF, the disease-specific conformational isoform of MIF (macrophage migration inhibitory factor). A two-step pretargeted radioimmunotherapy with cON-05 and a [177]Lu-labeled di-HSG peptide was tested in murine models of cancer. The treatment was well tolerated and led to significant tumor regression in colorectal cancer syngrafts and tumor growth inhibition in pancreatic cancer xenografts.

We report that IL-36 signaling can modulate neutrophils in a cell-intrinsic manner to greatly enhance their ability to directly kill tumor cells and to promote T cell proliferation. While poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the therapeutic potential of IL-36 to modify tumor-infiltrating neutrophils into potent effector cells and engage both innate and adaptive immune system to achieve durable anti-tumor responses.

Discovering therapeutic-quality antibodies for integral membrane protein targets is still a formidable challenge. To address this challenge, Abilita has developed the EMP technology, which dramatically improves target properties without impacting physiological relevance. Using CCR8, an immuno-oncology GPCR target, as a case study, we enabled protein-based approaches that led to the isolation of large families of antagonistic VHH antibodies binding to transmembrane epitopes.

• Recent advances in GPC2 and GPC1 as new targets in solid tumors
• Engineering CAR T cells for treating neuroblastoma and pancreatic cancers
• New strategies using camel nanobodies to improve efficacy of CAR T cells
  

ONix (oncoimmuneaccelerator) is a novel peptide that includes a variant of the SIRP-gamma extracellular domain (GV3) and a high affinity construct (HAC) of the soluble PD-1 extracellular domain. ONIx binds CD47 and PD-L1 in human, mouse, and dog cells, effectively displacing antibodies against these receptors. We have shown that ONIx is safe and has anti-tumor activity in mouse models. We are evaluating ONIx combined with an oncolytic VSV in two independent clinical studies of dogs with naturally occurring, advanced osteosarcomas and diffuse large B cell lymphomas that have failed first-line therapy. Preliminary signals of safety and biological activity are encouraging.

Immune-Onc Therapeutics (“Immune-Onc”) has a differentiated pipeline with a current focus on targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB) of myeloid checkpoints. These include IO-108, an antagonist antibody targeting LILRB2 (ILT4), in Phase I clinical development for solid tumors and IO-202; an antagonist antibody targeting LILRB4 (ILT3), in Phase I clinical development for the treatment of acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and solid tumors. Additional assets in Immune-Onc’s pipeline include IO-106, a first-in-class antagonist antibody targeting LAIR1; IO-312, a novel bispecific antibody targeting LILRB4 and CD3 (LILRB4 x CD3); and multiple undisclosed programs.

The immune checkpoint LAG3 was recently validated as a target for next-generation immunotherapies, but its molecular mechanism is poorly understood. We used yeast display to evolve LAG3 variants with enhanced biochemical behavior, thereby enabling us to determine structures of LAG3 ectodomains. We conducted structure-function studies of LAG3 interactions with antibodies and the ligands, MHCII and FGL1. This work provides insight into the rational development of LAG3-based therapeutics.

Cereblon (CRBN) has been known as a multi-functional signaling regulator in various cellular events. Nevertheless, less is known about the function of CRBN in lung cancer development and progression. Here, I show that CRBN is downregulated in lung cancer and negatively regulates TLR2, 4 and 7 stimulation in lung cancer cells. Thus, CRBN can be a potent prognostic marker for lung cancer and provides important implications in clinical and translational lung cancer biology.

Macrophages are often the most common infiltrating immune cell in tumors. New therapies that target macrophage immune checkpoints, such as CD47/SIRPa, show promise in clinical trials for solid and hematologic malignancies. These drugs may work best when used with other anti-cancer agents, but the optimal combination strategies have not been determined. Here, we present unbiased screening efforts to identify novel small molecules and biologics that enhance macrophage anti-tumor function.

Resistance to checkpoint inhibitor (CPI) therapy is in part due to immunosuppression created by tumor-associated macrophages (TAMs). OncoResponse uses a proprietary B cell screening platform to identify autoantibodies from patients with excellent response to CPI therapy that may reverse immunosuppression caused by TAMs. OR2805 is a first-in-class clinical antibody directed against CD163 that reverses immunosuppression caused by TAMs and restores T cell function, both in vitro and in vivo. OR502 is a preclinical anti- LILRB2/IL4 antibody that rescues T cells from macrophage-mediated suppression and induces anti-tumor responses.

FLT3 signaling is required for the differentiation and expansion of dendritic cells. For cancer immunity, conventional dendritic cell subtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mouse preclinical models. In human tumors cDC1 are often underrepresented in the tumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor efficacy. GS-3583 is a fusion protein composed of the extracellular domain (ECD) of human FLT3 ligand (FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583 is a promising immunotherapy candidate.