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MGD014 is a bispecific Dual-Affinity Re-Targeting, or DART®, molecule that targets the envelope protein of HIV-infected cells (Env) and CD3-expressing T cells. MGD014 is being developed by MacroGenics under a contract awarded in September 2015 by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. MGD014 is the first DART molecule targeting an infectious agent that is planned for clinical testing. The work under the contract will build on both recently published preclinical studies demonstrating that DART molecules targeting the Env and T cells, via their CD3 component, are able to redirect the immune system’s T cells to kill HIV-infected cells. DART molecules could be used independently or become a key part of a “shock-and-kill” strategy in conjunction with HIV latency-reversing agents currently under development. An Investigational New Drug (IND) application for MGD014 was submitted in 2017.
Two papers highlighting pre-clinical work on HIV-targeting DART molecules were published in October 2015. The first appeared in the Journal of Clinical Investigation, which first appeared online in September, demonstrated the potential of DART molecules as part of a “shock-and-kill” strategy against HIV. Two DART molecules developed at MacroGenics in collaboration with Duke University School of Medicine and the University of North Carolina at Chapel Hill (UNC) showed the ability to redirect T cells to kill cells infected by HIV isolates derived from subjects on continuous antiretroviral therapy, and to induce the killing of HIV-infected cells obtained from subjects following ex vivo induction of virus expression with a latency-reversing agent.
The second paper, appearing in PLOS Pathogens, reported that engineered molecules recruiting killer T cells to target HIV-infected cells expressing Env can induce killing of the HIV-infected cells. Working on the “kill” step, a team of researchers at MacroGenics and Gilead Sciences designed and evaluated DART molecules derived from broadly reactive anti-Env antibodies. These DART molecules were reactive against cells infected with diverse HIV isolates and were capable of reducing the level of HIV expression ex vivo in blood cells isolated from HIV-infected participants on suppressive antiretroviral therapy.
The initial phase of the work under the NIAID contract is to advance a first DART molecule (MGD014) through Investigational New Drug (IND) application submission. Pre-clinical IND-enabling studies will include collaborations with investigators at Duke University and the University of North Carolina, Chapel-Hill. NIAID may also exercise options to advance MGD014 into Phase 1/2 clinical trials as well as develop and test a second DART molecule. A third clinical trial would evaluate one of the DART molecules in combination with a latency reversing agent.
The development of a DART molecule targeting HIV is funded in part by NIAID under contract no. HHSN272201500032C.
MacroGenics retains full worldwide rights to MGD014.