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


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.]