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DART Platform

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DART™ Platform

MacroGenics has developed the Dual-Affinity Re-Targeting (DART) platform technology, which is focused on dual specificity “antibody-like” therapeutic proteins capable of targeting multiple different epitopes with a single recombinant molecule. To date, the company has produced over 100 different DART molecules and has completed in vitro and in vivo proof of concept studies. MacroGenics has established and continues to expand a patent estate around the DART technology.

The DART platform has been specifically engineered to accommodate virtually any variable region sequence in a “plug-and-play” fashion with predictable expression, folding, and antigen recognition. A key technological advancement and distinguishing feature of MacroGenics’ DART is a proprietary covalent linkage which results in a molecule having superior stability, optimal heavy and light chain pairing and predictable antigen recognition. MacroGenics believes that its minimal linker size and content decreases the potential for immunogenicity.

MacroGenics has created several different DART variants for the purposes of extending serum half-life and increasing avidity.

The DART platform is highly flexible and yields an array of product possibilities including, but not limited to: 1) modulation of receptor signaling events, 2) redirected effector cell killing, 3) targeting multiple cytokines or receptor ligands with a single molecule, and 4) targeting multiple epitopes on a pathogen for enhanced neutralization and/or clearance. MacroGenics has developed proof-of-concept data and is developing specific product candidates using this technology. The company has been able to produce DART molecules in both bacterial and mammalian expression systems.

Below are three illustrative DART modalities.

 

Publication in Blood: Comparison of DART vs. BiTE

In April 2011, the journal Blood published MacroGenics' 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 MacroGenics’ 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 was observed in the absence of engagement with targeted CD19-positive cells.  In addition, a CD19xTCR DART, constructed using a proprietary anti-T cell receptor antibody fragment, revealed virtually identical in vitro activity to that of the CD19xCD3 DART 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 as well as other recently published articles related to MacroGenics’ DART molecules “underscore 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 MacroGenics’ DART “…can be produced in high quantity and quality and reveals exceptional stability in both formulation buffer and human serum.”


DART Collaborations

In October 2010, MacroGenics announced that it had entered into two separate global strategic collaborations with Boehringer Ingelheim and Pfizer on its proprietary DART platform.  These deals position MacroGenics as a leader in the bi-specific antibody space, which is emerging as one of the core platforms for next-generation antibody products.  Across both deals, the scope is confined to a defined set of up to 12 specific target combinations.  MacroGenics continues to seek alliance partners for the development of DART-based therapeutics.