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Background
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.
DART® Platform
We use our DART platform to create derivatives of antibodies with the ability to bind to two distinct targets instead of a single one found in traditional monoclonal antibodies. DART product candidates are therefore bispecific.
For many years, researchers have sought to create recombinant molecules that are capable of targeting two antigens or epitopes within the same molecule. The challenges in creating such molecules have been the instability of the resulting bispecific molecules and their inherently short half-lives, as well as the inefficiencies in manufacturing these compounds. We believe our DART platform has overcome these engineering challenges by incorporating proprietary covalent di-sulfide linkages and particular amino acid sequences that efficiently pair the chains of the DART molecule. This is designed to provide a structure with enhanced manufacturability, long-term structural stability and the ability to tailor the half-lives of the DART molecules to their clinical needs. This engineered antibody-like protein has a compact and stable structure and enables the targeting of two different antigens with a single recombinant molecule. In addition, the DART platform has been specifically engineered to accommodate virtually any variable region sequence with predictable expression, folding and antigen recognition.
Potential mechanistic applications of the DART platform include:
- Redirected T cell activation and killing. A DART molecule designed to enable 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. An example from MacroGenics’ pipeline being evaluated in clinical trials is flotetuzumab.
- Simultaneous targeting of multiple co-inhibitory receptors or checkpoints, such as those involved in inhibiting T cell responses. Combinations of multiple checkpoint inhibitors have resulted in significantly enhanced benefit compared to the blockade of a single target. We believe that DART molecules targeting two immunoregulatory pathways, such as two checkpoints in a single molecule, 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. Examples from MacroGenics’ pipeline being evaluated in clinical trials include tebotelimab (being developed for co-blockade of PD-1 and LAG-3) and MGD019 (designed to enable co-blockade of PD-1 and CTLA-4).
TRIDENT® Platform
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.