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Optimising CAR-T and T-cell antibody engagers in haematological and solid tumours
Optimising CAR-T and T-cell antibody engagers in haematological and solid tumours
David Mead, Director of Business Development at Isogenica and Advisory Board Member of BioPartner UK, explains how VHH single-domain antibodies are prime to become integral components of next generation CAR-T and bispecific T-cell engager therapeutics.
The past ten years have seen a rapid evolution of therapeutic T-cell redirection immunotherapies, culminating in the approval of two important new treatment modalities: Chimeric Antigen Receptor T-cells (CAR-T) and Bispecific T-cell Engagers (BiTEs). One BiTE and three CAR-T therapies have been approved by the FDA for the treatment of haematological malignancies by direct redirection of T-cells. Despite positive clinical results, both therapies continue to face similar safety concerns due to the risk of cytokine release syndrome and neurotoxicity. CAR-T and antibody-based T-cell engager therapies are in development for solid tumours, but to date there are no approved therapies for treatment.
Significant possibilities exist to optimise both BiTEs and CAR-T through the incorporation of humanised camelid-derived single domain antibodies, commonly referred to as VHH or Nanobodies. VHH represent an attractive format for incorporation in CAR-T and T-cell engaging therapeutic format with carefully designed affinities, valencies and specificities enabling refined tumour cell targeting and modes of action. They are small, fully functional, single domain antibodies that exhibit all of the features associated with antibody specificity and have binding capacities like conventional monoclonal IgG antibodies. However, because of their smaller binding region, they can target antigens and epitopes that are considered intractable.
VHH domains are less immunogenic than other single chain constructs such as ScFv because of their high homology with human VH genes and absence of exposed hydrophobic regions making them less potent immune targets. Their small size, approximately 1/10th the size of an IgG molecule, is likely to enable improved tissue penetration in vivo. Because they are encoded by only a single gene, VHH can be easily covalently linked to other molecules or pro-drugs. Fusion of VHH that bind different epitopes or have different modes of action allows the creation of multivalent molecules with high affinity or potency. VHH can be engineered to tune their binding selectivity and specificity for antigen targeting, whilst their favourable biophysical properties simplify development and manufacturing. Their small size also confers advantages for tuning the immune synapse, the interface between antigen-presenting cells and T-cells, to optimise potency and minimise toxicity of T-cell redirecting immunotherapies.
Emerging evidence of how receptors at the immune synapse must be organised to optimise signalling elements for directed T-cell mediated killing highlights the importance of small format antibodies, such as VHH, in enhancing bispecific antibody T-cell engagers and CAR-T therapies. Isogenica’s overarching mission is to develop next-generation biotherapeutics to address unmet needs and improve clinical outcomes for patients. With a track record of delivering clinical assets through collaborative partnerships, discovery projects are tailored to achieve developable therapeutic candidate binders identified from its hugely diverse proprietary LlamdA® single domain antibody library. Purely in vitro, Isogenica’s LlamdA Library enables speed and efficiency unmatched by animal immunisation.
The company’s extensive expertise and technologies combine together to effectively develop novel approaches to disease treatment. Bringing these clinically proven technologies together – by the incorporation of VHH into bispecific antibody T-cell engagers and CAR-T – offers a highly promising route to next generation T-cell redirecting therapies that more effectively harness the immune system to fight cancer.
