Despite the exciting clinical benefits of immune checkpoint inhibitors, only a minority of cancer patients respond. We integrate AI, functional genomics, and cancer immunology for drug discovery. Our STEAD platform computationally extracts antibodies from patient tumor RNA-seq profiles and pairs targets with antibodies in silico. Our lead program, GV20-0251, targets novel checkpoint IGSF8 and reached IND in three years, demonstrating favorable safety and promising monotherapy efficacy in metastatic cancer patients.

Glypican-2 (GPC2), an oncofetal antigen expressed in childhood cancers such as neuroblastoma, is a new target whose inhibition blocks Wnt/ß-catenin signaling and N-Myc activity. I will also describe the engineering of T cells expressing novel antibody–TCR hybrids that incorporate a humanized CT3 Fab specific for GPC2, linked to TCR gamma and delta chains. These cells outperform CAR T cells in low-antigen tumors and have broad potential for solid tumor therapy.

The audience will gain insights into how Envisagenics' SpliceCore platform leverages AI to discover and validate novel, tumor-specific targets through alternative splicing, offering a new approach to immunotherapy development. This presentation will walk the audience through the end-to-end process from target discovery to rigorous target validation showcasing SpliceCore's ability to identify actionable therapeutic targets with high specificity and safety.

Complementing Immatics’ broad PRAME franchise, the presented T cell receptor bispecific (TCER) is directed against the stromal pHLA target COL6A3 Exon 6, aiming to disrupt the cancer’s protective barrier providing an innovative approach for cancer treatment. TCR potency and specificity are assessed throughout TCR identification and TCER engineering, demonstrating strong thermal stability, high affinity target binding and killing of target positive tumor cell lines.

Tumor-associated carbohydrate antigens (TACAs) are defined oligosaccharide structures, derived from changes in glycosylation pathways, that are expressed on the surface of cancer cells. Tacalyx develops antibodies against these difficult-to-target structures with the goal of spearheading the next generation of targeted anti-cancer therapeutics and will present its advancements in their current lead programs.

Most targeted cancer therapies rely on proteins overexpressed on tumors, but these are rarely truly cancer-specific, limiting safety and efficacy. GO Therapeutics leverages cancer-selective aberrant O-glycosylation to overcome this limitation. Using high-resolution O-glycoproteomics, we have defined tumor-restricted Tn-glycoepitopes on a large set of targets, including MUC1, MUC4, cMET, LAMP1, and CD44. Antibodies and ADCs directed to these glycoforms show high selectivity, potent in vivo cytotoxicity, negligible normal-tissue reactivity, and favorable cynomolgus toxicology, supporting clinical translation of this glyco-targeting platform.

Cell–surface proteins are key regulators of cellular activity, and one promising way to modulate their function is by controlling endocytosis. Under physiological conditions, cells use endocytosis to maintain homeostasis and tune signaling, yet its therapeutic potential is only beginning to be explored. I will discuss how bispecific antibodies can be designed to modularly control membrane protein endocytosis and signalling, their underlying mechanisms, and the potential therapeutic applications of these molecules.

ENPP1 suppresses cGAS–STING–mediated antitumor immunity by degrading extracellular cGAMP. Here, we characterize a therapeutic nanobody (B7) targeting ENPP1 that limits tumor progression in vivo. B7 antagonizes ENPP1 function in breast cancer cell assays and binds recombinant human and mouse ENPP1. Cryo-EM reveals engagement of the ENPP1 nuclease-like domain. Ongoing work focuses on mechanistic dissection and structure-guided nanobody optimization for therapeutic development.

TCR-mimics (TRCm) are new modular biologics that target peptide-HLA complexes to recapitulate TCR-like binding specificity. This new platformizable modality expands the reach of biologics to the intracellular proteome displayed on the surface of cells, and drive tumor cell killing through engineered effector modalities. Emerging strategies exploit TCRm and the peptide-HLA adducts of covalent small-molecules against defined oncogenic targets, enabling a unique combination that may finally realize Ehrlich’s “magic bullet".

The growing diversity of antibody scaffolds—DARPins, nanobodies, affibodies, miniproteins, and engineered fragments—is reshaping how we reach challenging intra- and extracellular targets. This Roundtable will explore 

• How scaffold architecture influences target engagement, pharmacokinetics, tissue penetration, and intracellular access
• Design trade-offs between stability, size, and function
• How next-generation scaffolds are unlocking previously inaccessible biology in oncology and beyond.​

Immuto Scientific has advanced technologies that identify cancer-specific protein conformations, called Surface Protein Conformers (SPCs), which expose epitopes that do not present in healthy cells. SPC target discovery through structural proteomics is combined with AI-powered antibody engineering, enabling the development of next-generation biologics, such as ADCs and multispecifics, tailored for precise disease intervention with a much lower risk of off-disease toxicity. The SPC technology provides a key advantage by unlocking previously inaccessible therapeutic targets in challenging indications, like hematologic malignancy and lung cancer.

DepMap systematically links tumor alterations to gene essentiality, supporting both basic and translational research. Many identified dependencies are now under validation or in clinical trials. Our recent work revealed a synthetic lethal interaction between the PELO/HBS1L and SKI complexes, suggesting PELO as a target in SKI-deficient cancers. DepMap continues to expand incorporating organoid models, new multi-omics data modalities, and new features towards the goal of accelerating precision cancer medicine.

Radiopharmaceutical therapy (RPT) is rapidly advancing; however, its progress has been limited by a narrow range of validated targets such as SSTR and PSMA. To achieve further breakthroughs, RPT development must expand toward new target-based programs and a deeper understanding of their mechanisms of action, grounded in translational oncology and multi-omics studies. Emerging methodologies that integrate human tumor atlas data, spatial biology, and AI-driven modeling enable systematic identification of novel targets and optimization of theranostic strategies. Together, these insights provide a scalable, data-driven roadmap for next-generation RPTs that complement existing antibody–drug conjugate and small-molecule modalities.

Peptide-HLAs are highly diverse tumor targets normally recognized by patient T cell immune responses. These targets can be discovered and targeted in solid tumors by leveraging off-the-shelf bispecific T cell engager therapies. We utilize an antibody-based discovery platform combined with high-throughput specificity mapping at the molecular resolution to develop highly potent T cell engagers. Preventing off-target specificity can ultimately improve the therapeutic index against pHLA targets.

Ocular neovascularization causes severe vision loss and is driven by the upregulation of vascular endothelial growth factor (VEGF) ligands; hence therapeutics that antagonize VEGF proteins have greatly advanced ocular disease treatment. However, many patients do not show benefit, in part since current therapies do not comprehensively block VEGF activity. We introduce 2 promising bispecific receptor decoy proteins that inhibit all VEGF ligands and significantly reduce ocular neovascularization in animal models.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder characterized by myeloid cell dysfunction, excessive pulmonary surfactant accumulation, and impaired innate immunity, primarily resulting from autoantibodies targeting GM-CSF, a cytokine essential for alveolar macrophage function. In this talk, the development of bispecific GM-CSF receptor agonists engineered to resist neutralization by polyclonal autoantibodies will be presented. These novel agonists effectively restore the functional capacity of macrophages and neutrophils, offering a promising therapeutic strategy for overcoming immune dysregulation in aPAP.

Heart disease and cancer—the two leading causes of death—share fibrosis as a common culprit. ANTXR1/TEM8, a pathology-induced protein critical for collagen turnover, drives both tumor growth and heart injury. This lecture shows how ANTXR1-neutralizing antibodies, originally developed for cancer, also protect the heart after myocardial infarction or pressure overload—reversing damage, restoring function, and revealing a shared mechanism linking two of humanity’s deadliest diseases.

The challenge of protein misfolding disease is targeting the often-scarce misfolded and pathological forms of the protein that cause disease, while avoiding the abundant, healthy form which performs important roles in the body. At Paradox Immunotherapeutics, we utilize a validated, structure-based approach to predict misfolding-specific epitopes to generate antibodies that target pathological proteins for clearance while avoiding the natively-folded species to improve organ function in systemic amyloidosis.