Alphamer technology, proprietary to Centauri Therapeutics and licensed exclusively to Avvinity Therapeutics for oncology applications, is based on chemically synthesized molecules that fuse modified nucleic acid aptamers against proteins overexpressed on the surface of tumor cells with alpha-gal epitopes: a trisaccharide present on the membranes of many organisms, but absent in humans due to the mutation of the GGTA1 gene in evolution.
The Alphamers then recruit naturally occurring antibodies directed against alpha-gal, which are present and abundant in almost all humans, triggering the body’s existing T-cell machinery to attack the attached cancer cell. Considerable investment has been made in the Alphamer technology since 2011, and it has been demonstrated through work in infectious disease1 that Alphamers have the potential to redirect pre-existing antibodies to bacteria in a specific manner, triggering an immediate antibacterial immune response.
While anti-gal antibodies are abundant, they have low affinity. This means that Alphamers can exploit avidity effects enabling productive binding preferentially to cells overexpressing the target whereas those with moderate target expression will not be productively engaged. To explore the utility of this approach, we have selected a number of initial targets for initial work for which there is high expression of a cell surface protein in a cancer or haematological malignancy, but generally low expression in normal tissues.
Alphamers promise key advantages over conventional antibody and antibody-drug conjugate molecules in immuno-oncology applications, including the ability to target cancers driven by both wild type (“normal”) gene overexpression as well as mutant (”abnormal”) gene overexpression, and by exhibiting a short half-life in the body, yielding reduced toxicity and systemic side-effects.
An additional benefit to our approach is that aptamers are made from modified nucleic acids and have well understood mechanisms of elimination, and so the pharmacokinetics of Alphamers can be predicted and tuned more easily than can conventional small molecules. This then is a very promising model for the development of new cancer therapeutics as Alphamers allow anti-gal antibodies to be recruited to the surface of cancer cells, which is anticipated to evoke a powerful, multi-pronged immune response.
1. Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer. Kristian SA, Hwang JH, Hall B, Leire E, Iacomini J, Old R, Galili U, Roberts C, Mullis KB, Westby M, Nizet V. J Mol Med (Berl). 2015 Jun;93(6):619-31
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