The Next Generation of Immuno-Oncology
Science
Uncovering and Exploiting novel antigens
Multiple sTA are identified on a single tumor cell and on a broad range of different cancer types. sTA are intracellular proteins in normal cells that locate to the surface of tumor and critical pro-tumor TME cells including cancer associated fibroblasts (CAF) subtypes.
Sustained cellular stress such as hypoxia, nutrient deprivation or continuous high protein production and proliferation within the TME results in endoplasmic reticulum (ER) and mitochondrial stress and survival responses such as the unfolded protein response (UPR). Unconventional secretory pathways result in modifications occur at the cell surface and at the surface of extracellular vesicles. Thus proteins restricted to intracellular sites in normal cells locate to the surface of tumor and protumor TME cells to support their survival. These sTA provide novel cancer antigens for immunotherapeutics and ideal targets due to their tumor survival roles. Their restricted intracellular expression in normal cells enables maximally effective drug dosing without severe toxicities due to on-target off-tumor/TME cytotoxic activity. A pilot safety study indicates that sTA specific immunotherapeutics are well tolerated.
Targeting a tumor cell’s Achilles’ heel
One sTA appears to be localized at the leading and trailing edge, the “foot” of a migrating tumor cell (figure). A monospecific antibody targeting this tumor antigen significantly inhibits tumor growth in animal studies. This antibody is engineered as not to support an immune cell response, thus binding the target sTA appears to suffice for tumor growth inhibition. Targeting the leading or trailing edge of a tumor cell can focus treatment to tumor cells that are actively involved in invasion and metastasis, the most lethal aspects of cancer.
A tumor antigen, with a predominantly diffuse punctate pattern on non-adherent tumor cells (left panel), concentrates at cell edges with spreading (center panel; arrows). The tumor antigen distribution is consistent with the leading and trailing edge, or” foot” of tumor cells with a migratory morphology (right panel; arrows).
Left and center panel; a non-adherent and adherent colon tumor cell line was stained with a Synergy IMT antibody specific for the tumor antigen(green). Red stain (propidium iodide) indicates a large non-viable cell.
Right panel; a breast tumor cell line, was stained with a cell permeant mitochondrial stain (red), PFA fixed and stained with Synergy IMT antibody specific for a novel tumor antigen (green).
Demonstrating their promise
A Foundation for Success
New tumor target antigens are desperately needed to address tumor heterogeneity, drug resistance, and the pro-tumor microenvironment. Drug candidates targeting sTA demonstrate significant tumor growth inhibition in efficacy studies and safety in a multidose tolerability study. Administration of a sTA4 monospecific antibody, that does not recruit immune cells via Fc receptor engagement, suffices for significant tumor growth inhibition. Blood biomarkers have been identified for therapeutics targeting sTA. These tumor antigen properties ensure that therapeutic development is founded on targets that dictate the most promising clinical trajectory.
Monoclonal Antibody
Colon Tumor Xenograft Study
Dosed IV @10mg/kg
Antibody Drug Conjugate (MMAE)
Colon Tumor Xenograft study
Dosed IV @4mg/kg
Biomarkers
Synergy IMT antibodies efficiently capture sTA bearing extracellular vesicles (sTA-EV) in cancer patient blood. The sTA-EV are derived from tumor or TME cancer associated fibroblasts (CAF) as determined by immunophenotyping. This liquid biopsy serves as a non-invasive, dynamic method to monitor the patient’s response to therapy. These biomarkers may enable an earlier diagnosis for certain cancer types , improve patient stratification for clinical trials, and help guide treatment decisions, ultimately leading to better patient outcomes.
AI driven docking of Synergy IMT PD-L1 antibody showing a subset of antigen H-bond contacts.
Engineering Precision; A Multi-Modal Therapeutic Engine
The Therapeutic Engine
AI is integrated throughout discovery and development. It has accelerated the identification of Synergy IMT’s platform tumor targets, to design and optimize therapeutic molecular architecture and assist in epitope mapping. Modular therapeutic designs with different functional moieties are engineered that include antibody, ligand and recombinant protein domains. Comparative studies are conducted to identify and focus on candidates with the greatest potency and promise of inducing a safe and durable antitumor response.
Modality Suite: Monospecific Antibodies, ADCs and Recombinant Proteins
Monospecific antibodies, antibody drug conjugates (ADCs) and recombinant protein candidates, that target sTA, and/or their activity, demonstrate significant tumor growth inhibition in animal tumor models. These early in vivo studies used lower affinity antibodies relative to those used in in vitro models.
Bi- and Tri-specific Antibodies and TCEs
Bispecific and tri-specific antibodies, including T cell receptor engagers (TCEs), and T cell co-stimulators have been created that target sTA and potently kill a broad range of tumor cell types.
Docking of Synergy IMT B7H3 specific antibody showing a subset of CDR H-bond contacts.
Clinical Momentum and Partnership Focus
Several drug candidates are well tolerated in a pilot multi-dose toxicity study, supporting tumor-restricted antigen expression. Multiple patents have been filed that cover these candidates and their novel targets.
Synergy IMT is focused on progressing an initial candidate into clinical studies and forming collaborations.