On December 22, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported the publication of a manuscript on MGD019, an investigational PD-1 × CTLA-4 bispecific DART molecule, in Cell Reports Medicine (Press release, MacroGenics, DEC 22, 2020, View Source [SID1234573205]). MacroGenics’ DART platform allows for the creation of bispecific antibody-based molecules with the ability to bind to two distinct targets in contrast to a single target as supported by traditional monoclonal antibodies.

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The publication, Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule, highlights key findings from the ongoing Phase 1 trial of MGD019 first-in-human study of patients with advanced solid tumors (NCT03761017) as well as data from mechanistic studies. Findings in mechanistic studies demonstrated that cells co-expressing PD-1 and CTLA-4 are abundant in the tumor microenvironment (TME) compared to normal tissues, supporting PD-1 and CTLA-4 co-blockade in treating solid tumor cancers. This observation suggests that targeting dual PD-1/CTLA-4-expressing cells may also provide an opportunity for increased selectivity of checkpoint blockade in the TME, while relatively reducing effects in normal tissues.

In vitro studies demonstrated that MGD019 may provide complete blockade of PD-1 together with tunable inhibition of CTLA-4, with greatly enhanced blockade of CTLA-4 activity on dual-antigen expressing cells, a potential advantage over PD-1 or CTLA-4 blockade with individual monoclonal antibodies. In addition, MGD019 was well tolerated in non-human primates following repeated intravenous (IV) administrations (four weekly doses) of MGD019 at dose levels of 10, 40 and 100 mg/kg, well exceeding the highest non-severely toxic dose reported for the combination of nivolumab and ipilimumab in this species.

These mechanistic data formed the basis for the on-going, first-in-human study demonstrating clinical activity and correlated pharmacodynamics. At the cutoff date of April 1, 2020, 33 patients representing 21 different advanced solid tumor types were treated, including 13 patients (39.4%) who had previously received checkpoint inhibitor therapy. Objective responses were reported in four patients (including one unconfirmed response) with tumor types typically unresponsive to conventional checkpoint inhibition. MGD019 was generally well-tolerated up to the top predefined dose level of 10 mg/kg, with no dose limiting toxicities (DLTs) observed and a safety profile generally consistent with that of anti-PD-1 monotherapy.

"Treatment with PD-1 and CTLA-4 inhibitors such as nivolumab and ipilimumab has been effective in several cancer indications; however, the combination is associated with significant toxicity," said Paul Moore, Ph.D., MacroGenics’ Vice President of Cell Biology and Immunology and the senior author on the paper. "The pre-clinical and clinical results published today demonstrated that MGD019 can mediate complete blockade of PD-1 with tunable blockade of CTLA-4, which is enhanced on dual-expressing cells, a potential advantage over blockade by combining individual monoclonal antibodies to PD-1 and CTLA-4. The early clinical data from the Phase 1 trial of MGD019 appear to indicate an acceptable safety profile and support further clinical investigation of MGD019 in cancer treatment."

About MGD019

MGD019 is an investigational, bispecific DART molecule that was designed to enable blockade of two immune checkpoint molecules expressed on T cells, PD-1 and CTLA-4. Based upon the establishment of a recommended Phase 2 dose (RP2D) from a dose escalation study, MGD019 is initially being evaluated in a dose expansion study in microsatellite-stable colorectal cancer and non-small cell lung cancer. MacroGenics retains global rights to MGD019.