A Phase 1, Randomized, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S, an Anti- Staphylococcus aureus Thiomab Antibody-Antibiotic Conjugate, in Healthy Volunteers

Abstract

Staphylococcus aureus causes serious bacterial infections with high morbidity and mortality, necessitating the discovery of new antibiotics. DSTA4637S is a novel antibody-antibiotic conjugate designed to target intracellular S. aureus that is not adequately eliminated by current standard-of-care antibiotics. DSTA4637S is composed of an anti-S. aureus Thiomab human immunoglobulin G1 (IgG1) monoclonal antibody linked to a novel rifamycin-class antibiotic (4-dimethylaminopiperidino-hydroxybenzoxazino rifamycin [dmDNA31]) via a protease-cleavable linker. Phagocytic cells ingest DSTA4637S-bound S. aureus, and intracellular cathepsins cleave the linker, releasing dmDNA31and killing intracellular S. aureus. This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 trial analyzed the safety, pharmacokinetics, and immunogenicity of DSTA4637S in healthy volunteers. Thirty healthy male and female volunteers, 18–65 years old, were randomized into five cohorts receiving single intravenous (i.v.) doses of 5, 15, 50, 100, and 150 mg/kg of DSTA4637S or placebo (4 active:2 placebo). Subjects were followed for 85 days after dosing. No subject withdrew from the study, and no serious or severe adverse events occurred. One moderate infusion-related reaction (150 mg/kg DSTA4637S) occurred. No clinically meaningful or dose-related changes in laboratory parameters or vital signs occurred. Pharmacokinetics of plasma DSTA4637S conjugate and serum DSTA4637S total antibody were dose proportional. Systemic exposure of unconjugated dmDNA31 was low. No DSTA4637S-induced anti-drug antibody responses were observed. DSTA4637S was generally safe and well tolerated as a single i.v. dose in healthy volunteers. DSTA4637S has a favorable safety and pharmacokinetic profile that supports future development as a novel therapeutic for S. aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02596399.)

Protease‐activated prodrugs: strategies, challenges, and future directions

“…The results demonstrated that the investigated DSTA4637A construct had almost no effect on noninfected mice and displayed a good PK/PD profile. Recently, this Ab–antibiotic conjugate was evaluated in phase 1 clinical trials in healthy volunteers, and the outcome was very promising, as no serious or severe adverse effects occurred . Moreover, no immune responses against DSTA4637S were observed, which confirmed the general hypothesis that such constructs should be safe for patients, as human cells do not express S. aureus antigens.…”

New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection

“…In a murine model of hematogenous MRSA infection, use of the AAC reduced S. aureus bacteremia relative to systemic vancomycin alone in both wild type and severe combined immune deficiency spontaneous mutation mice 23 . A similar approach showed no toxicity in human Phase I clinical trials 127 …”

“…Step 4, unconjugated dmDNA31 kills the intracellular bacteria. Reproduced with permission from: Peck et al 127 VS, valine‐citrulline [Color figure can be viewed at wileyonlinelibrary.com]…”

Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive

“…Of the 37 programs in the CARB-X portfolio for antibacterial treatment, over 48% are alternatives to traditional small molecule antibacterial agents [28]. Many products in various stages of development, from hit-to-lead to preclinical and clinical, that utilize these novel approaches are described in Table 2 [25][26][27][28][29][30][31][32][33][34][35][36][37][38]. [25,27] For example, monoclonal antibodies have revolutionized cancer chemotherapy [39,40] and have the potential to do the same for the treatment and prevention of infectious diseases [25][26][27].…”