Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against Staphylococcus aureus.

DSTA4637S, a novel THIOMAB™ antibody-antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy for complicated S. aureus bloodstream infections. DSTA4637S is composed of a monoclonal THIOMABTM IgG1 recognizing S. aureus linked to a rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. The pharmacokinetics (PK) of DSTA4637A (a liquid formulation of DSTA4637S) and its unconjugated antibody MSTA3852A were characterized in rats and monkeys. Systemic concentrations of three analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured to describe complex TAC PK in nonclinical studies. In rats and monkeys, following intravenous administration of a single dose of DSTA4637A, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential, characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested, and ac-dmDNA31 cleared 2-3 times faster than TAb. Unconjugated dmDNA31 plasma concentrations were low (<4 ng/mL) in every study regardless of dose. In this report, an integrated semi-mechanistic PK model for two analytes (TAb and ac-dmDNA31) was successfully developed and was able to well describe the complicated DSTA4637A PK in mice, rats and monkeys. DSTA4637S human PK was predicted reasonably well using this model with allometric scaling of PK parameters from monkey data. This work provides insights into PK behaviors of DSTA4637A in preclinical species and informs clinical translatability of these observed results and further clinical development. Abbreviations: ADC: Antibody-drug conjugate; AUCinf: time curve extrapolated to infinity; ac-dmDNA31: antibody-conjugated dmDNA31; Cmax: maximum concentration observed; DAR: drug-to-antibody ratio; CL: clearance; CLD: distribution clearance; CL1: systemic clearance of all DAR species; kDC: deconjugation rate constant; PK: Pharmacokinetics; IV: Intravenous; IgG: Immunoglobulin G; mAb: monoclonal antibody; S. aureus: Staphylococcus aureus; TAC: THIOMABTM antibody-antibiotic conjugate; TDC: THIOMABTM antibody-drug conjugate; TAb: total antibody; t1/2, λz: terminal half-life; vc linker: valine-citrulline linker; Vss: volume of distribution at steady state; Vc: volume of distribution for the central compartment; Vp: the volume of distribution for the peripheral compartment.

Absence from sera from normal individuals or from rifampin-treated leprosy patients (THELEP trials) of antibody to rifamycin-protein or rifamycin-membrane conjugates.

It has been reported that normal individuals have precipitating antibody which binds to rifamycin-conjugated proteins. An enzyme-linked immunosorbent assay has failed to confirm this claim, although antibodies demonstrable in a solid-phase binding assay are easily raised in mice if complete adjuvant is used. Moreover, no antibodies to rifamycin-protein conjugates were found in sera from the patients included in THELEP trials of six rifampin-containing regimens. Similarly, there was no antibody by the indirect Coombs test performed in another laboratory. Further studies using rifamycin-membrane conjugates regarded as more likely to be immunogenic in vivo also failed to reveal antibody in patients' sera, although this technique revealed an interesting antibody in one of four control sera known to be positive by the indirect Coombs test.

Pharmacokinetic assessment of immunosuppressive activity of antibiotics in human plasma by a modification of the mixed lymphocyte reaction.

Antibiotics may impair the development and expression of specific or nonspecific immune responses. Prophylactic administration of antibacterial antibiotics is widely used in ICUs. We studied the immunosuppressive activities of cefotaxime, chloramphenicol, gentamicin, metronidazole, and rifamycin as a function of time after the administration of these drugs to ICU patients, finding that the last 4 drugs had an immunosuppressive activity detectable up to 8 h by a mixed lymphocyte reaction. When these antimicrobial agents were added to normal pooled plasma in concentrations similar to those obtained in vivo, a similar degree of inhibition was observed.