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Our DART and TRIDENT platforms enable the creation of potential medicines comprised of a single molecule designed to simultaneously bind to two or more targets, each with antibody-like specificity, with the goal of creating a more significant biological effect than binding any one of the targets as with an antibody or even two or more of them separately as a combination. The versatility of these multi-specific platforms allows for the generation of antibody-based molecules with a variety of intended mechanisms of action. Today, several DART product candidates are being evaluated in clinical studies, with additional pre-clinical product candidates identified. The Company’s TRIDENT platform enables tri-specific targeting.
Key benefits of our platform include our ability to customize a DART molecule’s valency and half-life. These molecules also have the potential for improved safety profile through enhanced selectivity via bi-epitopic targeting and selective recruitment of specialized effector cells. In addition, our DART molecules are manufactured using a conventional antibody platform, typically at expression levels of grams-per-liter. And, in the case of our DART molecules that redirect T cells against cancer targets, this approach avoids the complexity of having to genetically modify T cells from individual patients as required by cell-based approaches such as with chimeric antigen receptor (CAR) T cells.
We have identified multiple potential mechanistic applications of the DART platform, including the four described below:
In April 2011, the journal Blood published our preclinical data demonstrating potent inhibition of B-cell lymphoma through redirected T lymphocyte-mediated killing, using bispecific DART antibody technology. Included in the peer-reviewed article is a side-by-side comparison of our DART protein to an antibody molecule identical in specificity and structure to that of a bispecific T-cell engager (BiTE), an alternative bispecific platform. While the previously established potency of the BiTE molecule in various redirected cytotoxicity assays was confirmed in this study, the DART was shown to be consistently more potent in eliminating CD19-positive cells. Importantly, no activation of T-cells by the DART molecule was observed in the absence of engagement with targeted CD19-positive cells. In addition, a T-cell receptor DART molecule targeting CD19, constructed using a proprietary anti-T cell receptor antibody fragment, revealed virtually identical in vitro activity to that of the CD19 x CD3 DART molecule and demonstrated in vivo activity in a xenograft mouse model.
An accompanying Inside Blood commentary titled “DARTs take aim at BiTEs,” noted that this article underscores “the adaptability of this bispecific antibody platform; it also provides an alternate T-cell recruiting and activation mechanism that may have a different activity and toxicity profile than blinatumomab.” The commentary further noted that a DART molecule “…can be produced in high quantity and quality and reveals exceptional stability in both formulation buffer and human serum.”
MacroGenics’ TRIDENT platform reflects the continuing evolution of the expertise we developed in creating our DART platform. Built on an Fc-bearing DART molecule, the tri-specific TRIDENT platform is an Ig-like format that incorporates an additional Fab domain capable of engaging an independent antigen. The inclusion of a third specificity allows for a much broader range of mechanisms of action than bispecific targeting, allowing, for instance, the engagement of multiple antigens on a single or on different cells or enabling enhanced target selectivity by modulating the avidity of one of two antigens.
® BiTE is a registered trademark of Amgen, Inc.