Emerging Targets for Oncology & Beyond

Patients’ B cell repertoires are unbeatable sources for antibody and target discovery. Kling Biotherapeutic’s technology overcomes the limited proliferative lifespan of primary human and animal B cells by transduction with a proprietary vector to express Bcl6 and Bcl-xL, which prevents both terminal differentiation and apoptosis while allowing the ability to undergo somatic-hypermutation in vitro. Here we present the generation of tumour-derived cell libraries for immediate functional screening and therapeutics design.

Macrophages are often the most common infiltrating immune cell in tumours. To engage these cells as effectors, we used surfaceome profiling data to engineer a compendium of 156 novel bispecific antibodies that target lymphoma cells and/or macrophages. We identified dozens of bispecifics that dramatically stimulate macrophage-mediated cytotoxicity of lymphoma cells. Our approach can be applied to other cancers or other immune cell subsets to rapidly engineer and validate bispecific antibodies.

Neuroinflammation is a hallmark of several neurodegenerative diseases, including Parkinson’s disease. Molecular machines known as inflammasomes, especially the NLRP3 inflammasome, sense misfolded proteins such as alpha-synuclein, resulting in caspase-1 activation, interleukin-1 cytokine production, and lytic cell death. During neuroinflammation, activated microglia release the inflammasome adaptor protein, ASC, outside the cell, where it is recognized as a ‘danger signal’ and functions to further propagate inflammatory responses. In this project, we have developed a panel of single-domain antibodies (sdAbs) that bind to the extracellular ASC and block its oligomerization, thereby preventing the consequent inflammasome activation. This will enable us to target both intracellular and extracellular inflammasome activation, thereby attenuating the propagation of inflammation in chronic neurodegenerative diseases.

Loss-of-function variants in INHBE, encoding Activin E, protect against obesity and Type 2 diabetes. Using a novel AI-enabled epitope steering platform, we developed a first-in-class anti-Activin E antibody. In diet-induced obese mice, treatment induced fat-selective weight loss, which was synergistically enhanced with a GLP-1 receptor agonist, highlighting its potential as a next-generation obesity therapy.

Immune mobilising monoclonal T cell receptors (TCRs) Against Virus (ImmTAV) are soluble TCR bispecific molecules that are engineered to bind viral peptide-human leukocyte antigen (pHLA) complexes with high affinity and to redirect specific killing of virus-infected cells via engagement of CD3 on polyclonal effector T cells. Here we present our strategy for engineering ImmTAV molecules to bind HLA-A*02:01 presented viral epitopes and overcoming complexities of targeting viral peptide variants.

Many Crohn’s disease patients are primary resistant to anti-TNFα therapy, with IL-13Rα2 overexpression driving this resistance. Affilogic’s GIJob project develops an orally administered anti-IL-13Rα2 Nanofitin to restore anti-TNFα therapy efficacy in primary resistant patients. The Nanofitin's high stability enables oral formulation. The candidate shows sub-nanomolar potency, resistance to gastrointestinal degradation, and oral in vivo efficacy in a murine colitis model, offering a promising solution for patients.

TROP2 is overexpressed in aggressive tumours, making it an important target in oncology. KJ-103, a novel naked heavy chain–only anti-TROP2 antibody from KisoJi’s technology platform, induces potent FcɣR-dependent anti-tumour activity and reshapes the TME by promoting pro-inflammatory macrophages, enhancing antigen presentation and T-cell-associated responses. It is well tolerated with a broad therapeutic window, supporting its use as monotherapy or with checkpoint inhibitors. Phase 1 trials are set for 2026.

Matrix Metalloproteinases 9 (MMP-9) have recently been implicated in glioblastoma progression, the most aggressive type of brain cancer with no cure. We present a drug candidate based on TIMP-2, an engineered human protein that selectively inhibits MMP-9 with picomolar affinity. Our protein effectively suppresses U251 glioblastoma cell proliferation and invasion while showing no cytotoxicity to healthy cells, thus presenting a new attractive strategy for drug development in glioblastoma.

Relaxin-2 has shown promising cardiovascular benefits in both preclinical models and clinical trials, however its therapeutic potential has been limited due to the short half-life. To address this, we have developed AZD3427, a novel fusion protein, which closely mimics the natural hormone's structure and consists of a single relaxin-2 and a heterodimeric Fc fragment. AZD3427 exhibits an improved pharmacokinetic profile, maintains the pharmacology of relaxin-2 in vitro and improves cardiac performance in an NHP model.