Identifying genuinely novel targets that have immense therapeutic potential is an increasing challenge across CNS diseases and oncology. Alchemab addresses this challenge by truly disrupting the target discovery process—simply put, we let the patient select the best targets. We have discovered novel disease-relevant targets through our proprietary platform that searches for protective auto-antibodies in patients who are resistant to disease.

Recent advances in antibody engineering have created a portfolio of highly potent therapeutic approaches like antibody-drug conjugates (ADCs), radioimmunoconjugates (RITs), chimeric antigen receptors (CARs), or bispecifics. Due to the increased potency, these drugs are more than ever dependent on very clean targets to prevent side effects. We aim to address this major problem through our approach to develop antibodies with improved tumor specificity and reduced on-target/off-tumor binding, utilizing the aberrant O-glycosylation on tumor cells. A workflow and corresponding database was established to evaluate the O-glycosylation of proteins. This information is subsequently used for targeted discovery of antibodies that bind to protein/carbohydrate combined glycoepitopes (GlycoTargets). A case study will be presented that highlights our workflow to identify suitable GlycoTargets and subsequent development of antibodies.

Most antibody tumor targeting strategies seek to differentiate between disease and normal tissue through the relative abundance of a tumor associated antigens (TAA). Protein dysregulation in cancer can create selective TAAs but such antigens are rare and heterogeneous across patients. While fluid, the cell surface has structure and loose organization of protein neighborhoods. Dysregulation in cancer cells can also result in re-localization of proteins into new neighborhoods. This context of protein neighborhoods provides an additional, underutilized targeting property. We have established a Membrane Interactomics (MInt) platform to identify unique Tumor Associated Proximity Antigens (TAPAs). Using MInt, we have identified several unique proximity-targeting tumor addresses which we have utilized for selective targeting of bispecific ADCs. TAPAs represent and exciting new class of tumor targets.

To overcome challenges in antibody discovery against ion channels and GPCRs, Maxion have developed a novel antibody fusion format (KnotBody), by fusing naturally occurring ion channel modulators (knottins) into peripheral CDR loops. This presentation will present our current progress towards developing safe, efficacious and long-acting drugs against previously undruggable targets.

This presentation will highlight the preclinical data supporting the development of BDC-3042, a first-in-class Dectin-2 agonistic antibody leading the way in tumor-associated macrophage-directed immunotherapy. This talk sheds light on the potential of harnessing the immune system against cancer through targeted macrophage modulation via a novel target, Dectin-2.

TIGIT-Fc-LIGHT was designed to block all TIGIT-ligand interactions, provide immune co-stimulation to CD8+ T and NK cells via HVEM and myeloid cells by LTBR, and broaden clinical responses into PDL1-low and CPI acquired resistance tumors. TIGIT-Fc-LIGHT differs from antibody blockade of TIGIT, since its co-stimulatory activity (HVEM and LTBR versus DNAM-1) is not directly inhibited by PD1 nor down-regulated on TIL in advanced tumors.

CAR-T cell therapies in solid tumors are limited by the lack of cancer-specific cell-surface targets. The oncofetal antigen CLDN6 is a promising target that shows high-level aberrant cell membrane expression in many solid tumors. I will discuss CLDN6, the preclinical and clinical anti-tumor activity and safety of CLDN6-targeting CAR-T cells (BNT211-01), and the effect of a CAR-T cell-amplifying RNA vaccine (CARVac) on CAR-T cell expansion and persistence.

I will discuss our recent studies on GPC1 and B7-H3 (CD276) as emerging cancer targets, as well as the engineering of CAR T cells for the treatment of pancreatic cancer and neuroblastoma. Additionally, I will describe nanobody technology and single-cell-based transcriptomic analysis of “polyfunctional” CAR T cells to enhance the efficacy of CAR T cell therapy.

ImmTAC bispecifics are designed to elicit a potent T cell response to kill tumor cells. Here we present engineering of IMC-R117C, targeting a peptide derived from PIWIL1, a novel colorectal cancer target, in complex with HLA-A2. We used a proprietary TCR-phage library to identify an optimal TCR with supraphysiological affinity, and an affinity engineering approach that ensures reduced off-target binding; a common challenge with pHLA targeting molecules.

The immunosuppression of myeloid cells and lymphocytes within the tumor microenvironment limits efficacy of checkpoint inhibitors. LILRB1 and LILRB2 are inhibitory receptors on immune cells that interact with ligands including HLA Class I and promote an immunosuppressive phenotype of myeloid cells and inhibit T and NK cell cytotoxic activity required for tumor cell death. Dual antagonism of LILRB1 and LILRB2 is a promising strategy to enhance efficacy of checkpoint inhibitors. We have identified OR641 as a dual antagonist antibody that demonstrates superior activity in relieving LILRB1- and LILRB2-mediated immune suppression and enhances both innate and adaptive anti-tumor immunity.

A critical cancer driver is MYC, a non-redundant transcription factor essential for cancer cell proliferation and survival. Despite the high interest for a clinical MYC inhibitor, no such drug is currently available, mainly because of the challenges of drugging an intrinsically disordered target localized in the cell’s nuclei. OMO-103, an intravenously delivered cell-penetrating mini-protein, is the first direct MYC inhibitor to have successfully overcome these challenges and completed a clinical trial in human patients showing safety and first signs of clinical activity, supported by molecular target engagement. Here, we present the preclinical development and results from this first-in-human clinical study.

The anti-NRP-1 antibody “NOV2”, specific to leptin binding domain presents a unique mode of action. It enters cancer cells nuclei to induce their DNA damage and activates thus the anti-tumor response by increasing the number of Tumor Infiltrating CD4+T lymphocytes and CD8+T lymphocytes activation in correlation with metastasis decrease. NOV2 represents a great therapeutic tool for Targeting DNA Damage Response Immuno-Oncology.

Regulatory T cells are necessary for preventing autoimmune disease but may also inhibit cytolytic T cells in the tumor microenvironment. Reducing tumor-specific Tregs without compromising systemic tolerance has been challenging. CCR8, a chemokine receptor highly expressed on Tregs in solid tumors, serves as an ideal target for ADCC-mediated depletion, leading to robust anti-tumor immunity as a monotherapy as well as in combination with multiple complementary anti-tumor agents.

Sutro's proprietary cell-free protein synthesis and site-specific conjugation platforms enable homogeneous ADCs with best-in-class potential. STRO-004 is a tissue factor-targeting ADC with a stable beta-glucoronidase cleavable linker and TOPO-1 inhibiting Exatecan warhead, precisely positioned by non-natural amino acids with a drug-antibody ratio of 4. STRO-004 demonstrates potent tissue factor-dependent tumor killing in preclinical models and a favorable safety profile in non-human primates, providing a promising clinical candidate for solid-tumor indications.

Vaccination is generally ineffective against established disease. To overcome immune tolerance in cancer and chronic infection we’ve focused on stimulating the Antigen Presenting Cell by fusing cancer or viral antigens to antibody derivatives targeting and activating the APC-restricted receptor CD180. This coincident antigen delivery and APC activation via CD180 results in potent yet highly antigen-specific activation of both humoral and cellular response without collateral immune activation. These APC-activating fusion proteins delivering disease antigens clearly demonstrate the potential of this new immunotherapeutic platform.