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Immunotherapies for Life

Multimerization Technology is proven to be enhancing antibody respons

To further improve bispecific antibodies (BsAbs), we have licensed from MSK a novel human protein tag that dimerizes T-cell engaging BsAb by complexing them into identical pairs. This results in higher tumor binding, resulting in a longer serum half-life, and a significantly greater T-cell mediated killing of tumor cells, without inducing excessive cytokine release.

Many human proteins are dimeric and bivalent, which means that they are binding cooperatively to two targets at the same time. When it is bivalent, IgG crosslinks the targets it is binding to, and initiates a signaling cascade into the cell. When bivalent, IgG binds much stronger to its target and spends a much longer time attached to its prey. Well known in pharmacology, the longer you stay engaged, the longer the “residence time” on your target, and the more effective the drug will be.

With the advent of novel engineered miniature proteins such as bispecific T-cell engagers (BiTEs), the size of the protein is suboptimal. In order to avoid being excreted rapidly into the urine, intravenous therapeutic proteins have to be bigger than the renal threshold, that is, larger than 65,000 daltons in terms of size. Most BiTEs are around 55,000 daltons and therefore rapidly leak into the urine, and BiTE currently has to be given to patients as a continuous infusion over 4-8 weeks.

When dimerized into proteins of 110,000 daltons, BiTE is much more effective in vitro as a bivalent molecule. But more importantly, its serum half-life is substantially increased in animal models, translating into improved efficacy without the need of continuous infusion. We have designed a tag that fulfills these requirements, and this concept was proven in preclinical studies, and a patent concerning our Multimerization technologies has been filed.