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In vivo preclinical efficacy of MGD014 and MGD020 (HIV-1 envelope x CD3 DART molecules) and first-in-human phase 1 clinical safety evaluation of MGD014

Title
In vivo preclinical efficacy of MGD014 and MGD020 (HIV-1 envelope x CD3 DART molecules) and first-in-human phase 1 clinical safety evaluation of MGD014
Presenter
Jeffrey L. Nordstrom
Authors
J.L. Nordstrom * (1), C.L. Gay (2), C. Bohac (1), A.R. Wahl (3), T. Morgan (3), J.L. Schmitz (4), H. Li (1), J. Cotshott (1), J. Gobburu (5), A.N. Macintyre (6), R.J. Gorelick (7), G. Ferrari (8), D.M. Margolis (2), J.V. Garcia (3)
Institutions
(1) MacroGenics, Inc., Rockville, United States, (2) University of North Carolina at Chapel Hill School of Medicine, UNC HIV Cure Center and Department of Medicine, Chapel Hill, United States, (3) University of North Carolina at Chapel Hill, International Center for the Advancement of Translational Science, Division of Infectious Diseases and Center for AIDS Research, Chapel Hill, United States, (4) University of North Carolina at Chapel Hill School of Medicine, Department of Pathology and Lab Medicine, Chapel Hill, United States, (5) University of Maryland, School of Pharmacy and School of Medicine, Baltimore, United States, (6) Duke University, School of Medicine and Duke Human Vaccine Institute, Durham, United States, (7) Leidos Biomedical Research, Inc., AIDS and Cancer Virus Program, Frederick, United States, (8) Duke University, Department of Surgery and Department of Molecular Genetics and Microbiology, Durham, United States

BACKGROUND: MGD014 and MGD020 are bispecific DART® molecules that bind CD3 and HIV-1 env; anti-env specificities are from non-neutralizing mAbs A32 and 7B2, respectively. They redirect CD3+ T lymphocytes to kill HIV-1-infected CD4+ T cells. We evaluated the in vivo antiviral efficacy of MGD014 and MGD020 in HIV-1-infected humanized mice on antiretroviral therapy (ART). We also completed an initial phase 1 safety study of MGD014 in persons with HIV-1 (PWH) on ART [NCT03570918].
METHODS: MGD014 and MGD020 were administered (300 mcg/kg, QW) to HIV-1-infected humanized mice on ART. To assess the effects on cell-associated HIV-1 RNA (caRNA), tissues (spleen, liver, bone marrow, lymph node, organoid) were collected after 2 DART molecule doses. To assess the effects on rebound viremia, 7 DART molecule doses were administered; ART was discontinued after the 4th DART molecule dose. The MGD014 clinical study evaluated 21 participants in Part 1 (single dose escalation, 0.1 to 300 mcg/kg) and 3 participants in Part 2 (300 mcg/kg, Q2Wx3). Endpoints included incidence of DLTs, PK, ADA, cytokines, immunophenotype, and residual plasma viremia.
RESULTS: The efficacy study in HIV-1-infected humanized mice revealed that MGD014, MGD020, or MGD014+MGD020 [combination] reduced mean caRNA levels in tissues by 3.7-fold (p=0.0161), 1.9-fold (p=0.0132) or 6.2-fold (p <0.0001), respectively (Mann-Whitney test). Importantly, following ART discontinuation, median time to viremia rebound was 7 days for MGD014 (p=0.0444), 12 days for MGD020 (p=0.009) or 19 days for MGD014+MGD020 (p=0.0001) (Kaplan-Meier analysis). In the MGD014 clinical study, no DLT or SAE was observed. At 300 mcg/kg, MGD014 bound an average of 92% and 72% of circulating CD4+ and CD8+ T cells, respectively, without inducing activation markers or serum cytokines. MGD014 half-life was ~12 days and trough serum concentrations exceeded EC90 for redirected CD8+ T cell killing of HIV-infected CD4+ T cells in vitro by '¥ 20-fold.
CONCLUSIONS: Administration of MGD020+MGD014 mediated greater HIV-1 clearance activity than individual DART molecules in HIV-1-infected humanized mice. MGD014 was well-tolerated in PWH on ART. A first-in-human study with MGD020+MGD014 in PWH on ART will begin in 2022.Our data support future clinical studies combining DART molecules and latency reversing agents. [Funded by NIAID (HHSN272201500032C) and NCI (75N91019D00024) contracts.]