Advancing Multispecific Antibodies and Combination Therapy to the Clinic

Antibodies have revolutionised treatment paradigms for numerous diseases, but unfortunately this revolution is much more limited for central nervous system (CNS) disorders. One of the main reasons for this is that they have difficulties to pass the blood-brain barrier (BBB). Our research focusses on how to facilitate transport of biologics to the brain, and equally important, on how to extend the CNS half-life of antibodies once they’ve reached the brain.

The aim of therapeutic cancer vaccines is to induce tumour-specific T cell responses. This requires efficient processing and presentation of tumour antigens by antigen-presenting cells, in particular dendritic cells (DCs). We have developed several site-specific antibody conjugation strategies, which we have applied for DC-targeted delivery of peptide-based antigenic cargo, as well as targeted immunostimulatory adjuvant co-delivery approaches in preclinical in vivo models.

The field of multispecific antibodies is highly dynamic and expanding rapidly. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the unique biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This presentation highlights insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, and also focusses on the opportunities of molecular imaging studies to support and de-risk the clinical development of multispecific antibody therapies.

Deep B-cell tissue depletion may induce reset of autoimmunity and promote sustained drug-free remission. Assessing the depth of tissue B-cell depletion in peripheral tissues such as lymph nodes, bone marrow, and/or synovium has emerged as a reliable tool to assess the capacity of a therapeutic intervention to achieve the so-called immune reset in autoimmune diseases. Cell-based and protein-based B-cell depleters show different B-cell depleting capacity in peripheral tissues.

The therapeutic potential of T cell engagers (TCE) has been restricted by a narrow safety window, with excess cytokine release and on-target toxicity limiting their clinical usefulness. Our Tumour-Microenvironment Activated Therapeutics (T-MATE) platform overcomes these challenges by utilising a pH-dependent conformational switch. This innovative mechanism attenuates TCE activity at physiological pH while preserving full potency within the tumour microenvironment, enabling a new class of safe and effective TCE therapeutics.

ROSE12 is a novel, FcγRs affinity-enhanced anti-CTLA-4 antibody that is activated by high concentrations of extracellular ATP in the tumour microenvironment. ROSE12 exhibits strong, ATP-dependent ADCC activity that significantly surpasses that of a non-fucosylated-Fc anti-CTLA-4 antibody. In mouse models, ROSE12 selectively depleted intratumoural Tregs, demonstrating anti-tumour effects without triggering systemic immune activation. ROSE12 offers a potentially wider therapeutic window than conventional FcγRs affinity-enhanced anti-CTLA-4 antibodies and is currently undergoing phase 1 clinical trials for solid tumours.

T cell engagers (TCEs) have transformed the treatment of hematologic malignancies and are gaining traction in solid tumours. This presentation explores emerging mechanistic insights into TCE activity, focusing on glofitamab—a CD20xCD3 TCE approved for relapsed/refractory large B-cell lymphomas. Emphasis is placed on resistance mechanisms and combination strategies to enhance efficacy and guide the future optimisation of TCE-based therapies.

Clustering of the costimulatory TNF receptor superfamily member OX40 on activated T cells activates signaling pathways that enhance T cell activation, survival, and proliferation. First generation OX40 agonists requiring FcγR-mediated crosslinking to induce OX40 agonism have demonstrated limited clinical activity. HexaBody-OX40 (GEN1055/BNT315) is a next-generation investigational OX40 agonist antibody designed to cluster OX40 independent of FcγR-mediated crosslinking to enhance antitumour T cell responses.