Background
MGD014 and MGD020 are bispecific DART® molecules that bind CD3 and bind HIV-1 Env with specificities derived from non-neutralizing mAbs A32 and 7B2, respectively. They redirect CD3+ T lymphocytes to kill HIV-1-infected, Env-expressing CD4+ T cells. When administered to HIV-1-infected humanized mice on ART, the combination of MGD020+MGD014 reduced cell-associated viral RNA in tissues and delayed rebound following ART discontinuation. Alone or combined, MGD014 and MGD020 demonstrated acceptable safety in Persons with HIV-1 (PWH) on Antiretroviral Therapy (ART) (NCT03570918, NCT05261191). MGD014 and MGD020 did not induce significant changes in circulating cytokines and inflammatory cells. Studies with latency reversal strategies are underway. In this NCT05261191 companion study, immunological responses in gut-associated lymphoid tissue (GALT) in PWH receiving MGD020 or MGD020+MGD014 were assessed.
Methods
Participants in NCT05261191, who elected to co-enroll in this companion study, underwent GALT sampling prior to and after completion of study treatment in NCT05261191. GALT was analyzed via single-cell RNA sequencing (scRNA-seq) and flow cytometry.
Results
In NCT05261191, 15 PWH received a single escalating dose of MGD020, 6 received a single dose of MGD020 (100 or 300 µg/Kg) with 300 µg/Kg MGD014, the maximal dose established in NCT03570918, and 3 received multiple doses of both at 300 µg/Kg. There were no serious adverse events and no study discontinuations. 300 µg/Kg of MGD020 yielded a mean maximum serum concentration of 6415 µg/L (95% C.I. 5729-7101), mean half-life of 221 hours (95% C.I 94-348), and mean peripheral CD3 receptor occupancy of 13-14% (85-91% of CD4+ or CD8+ T cells). In the companion study, 5 participants (2 female, 3 male at birth) had baseline and follow-up GALT sampling; 4 received single-dose MGD020 [30 µg/kg (n=2) and 300 µg/kg (n=2)] and 1 received single-dose MGD020+MGD014 (100+300 µg/Kg). scRNAseq analysis of 52615 ileal and 49435 colonic cells showed that cytotoxic T cell or macrophage frequencies did not increase after treatment. Flow cytometry revealed stable frequencies of ileal and colonic neutrophils (CD66b+CD16+CD3-CD19- live cells) and monocyte-macrophages (CD14+ CD3-CD19- live cells) after treatment (Table 1).
Conclusions
Administration of MGD020 alone or in combination with MGD014 to PWH on ART does not appear to increase GALT inflammatory markers, providing additional reassurance of safety in vivo.
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