Home Antibody Technology PlatformsDART® and Trident™ Multi-Specific Platforms

Our Dual-Affinity Re-Targeting, or 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, five DART product candidates (MGD006, MGD007, MGD009, MGD011 and MGD010) are being evaluated in clinical studies, with several additional pre-clinical product candidates identified. The Company’s Trident platform enables tri-specific targeting.

DART Platform

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:

  • Redirected T cell activation and killing. This version of the DART molecule enables the cancer-fighting properties of the immune effector cells, such as T lymphocytes, to: (1) recognize and bind to structures expressed on a cancer cell, (2) recruit all types of cytotoxic, or cell killing, T cells, irrespective of their ability to recognize cancer cells, and (3) trigger T cell activation, expansion, and cell killing mechanisms to destroy a cancer cell. Examples from our pipeline include MGD006 and MGD011.
  • Modulation of receptor signaling. This configuration takes advantage of a single DART molecule’s ability to target two different specificities on a molecule or cell, which can be used to usurp signaling pathways programmed within the targeted molecule or cell. As an example from our pipeline, MGD010 is being developed to promote the interaction of CD32B and CD79B, a step required to interrupt the B-cell activation and immune response that single antibodies directed against CD32B, CD79B, or both cannot accomplish independently.
  • Simultaneous targeting of multiple co-inhibitory receptors or checkpoints, such as those involved in inhibiting T cell responses and B cell responses. Combinations of multiple checkpoint inhibitors have resulted in significantly enhanced benefit compared to the blockade of a single target. MGD013, which is being developed for co-blockade of PD-1 and LAG-3, could afford the clinical benefit of the combination together with the potential for synergistic activity, as well as significant advantages in manufacturing, simplified clinical development, and enhanced patient convenience.
  • Targeting multiple epitopes on a pathogen for enhanced neutralization and/or clearance.
    Creating DART molecules that neutralize multiple infectious variants of a virus or multiple toxins produced by a bacterium could be an advantage for prevention or treatment.

Publication in Blood: Comparison of DART vs. BiTE®

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.”

Trident Platform

MacroGenics’ Trident platform — introduced at our 2015 R&D Day — 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.

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