Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against<i>Staphylococcus aureus</i>

Deng, Rong; Zhou, Chenguang; Li, Dongwei; Cai, Hao; Sukumaran, Siddharth; Carrasco‐Triguero, Montserrat; Saad, Ola M.; Nazzal, Denise; Lowe, Christopher; Ramanujan, Saroja; Kamath, Amrita V.

doi:10.1080/19420862.2019.1627152

Cited by 28 publications

(24 citation statements)

References 35 publications

(61 reference statements)

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“…A literature search was conducted to find some more PK data for ADCs than reported by Li et al The search resulted in obtaining rat clearance data for DNIB0600A [ 12 ] and Polatuzumab vedotin [ 13 ], and mouse clearance data for brentuximab vedotin [ 14 ]. The PK data for thiomab and the anti-5T4 Antibody–Drug Conjugate was found in the literature with three animal species and humans [ 15 , 16 , 17 , 18 , 19 ]. Overall, there were seven ADCs for which three animal species and human clearance values were available for the scaling ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance

Mahmood¹

2021

Antibodies

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Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance with the observed human clearance. For three animal species allometric scaling, the “Rule of Exponents” (ROE) was used. The results of the study indicated that three-species allometric scaling in association with the ROE provides acceptable prediction (within 0.5–2-fold prediction error) of human clearance. The two-species allometric scaling resulted in substantial prediction error. One-species scaling using a fixed exponent of 1.0 provided acceptable prediction error (within 0.5–2-fold) by monkey, rat, and mouse, in which monkey and rat were comparable. Overall, the predicted human clearance values of ADCs from animal(s) was good. The allometric method proposed in this article can be used to predict human clearance from the animal data and subsequently to select the first-in-human dose of ADCs.

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Section: Methodsmentioning

confidence: 99%

Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance

Mahmood¹

2021

Antibodies

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“…MSTA3852A was selected from >40 anti-S. aureus antibodies that originated from the blood of patients recovering from different S. aureus infections. The highest level of binding by those antibodies was directed against a major component in the cell wall of S. aureus, the wallteichoic acids (WTAs) (Lehar et al, 2015;Deng et al, 2019).…”

Section: Synthesis Of Tnp-2092mentioning

confidence: 99%

“…V112C mutagenesis of the antibody MSTA3852A, in which a valine in the light chain IgG1 is precisely replaced by a reactive cysteine residue, enables site-specific conjugation with a drug-antibody ratio (DAR) of two vc-dmDNA31 per antibody (Deng et al, 2019). Site-specific conjugation in ADC enables a direct and homogeneous conjugation of a drug (Zhou, 2017).…”

Section: Synthesis Of Tnp-2092mentioning

confidence: 99%

“…The preclinical PK properties of TAC 23 were profiled in mice, rats, and cynomolgus monkey (Zhou et al, 2016;Deng et al, 2019). The PK profiling of TAC involved the analysis of three analytes: TAC total antibody (TAb) which includes fully conjugated (DAR 2), partially conjugated (DAR 1), and unconjugated antibodies (Zhou et al, 2016).…”

Section: Synthesis Of Tnp-2092mentioning

confidence: 99%

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Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

Surur

Sun

2021

Front. Chem.

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The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs—on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody–antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.

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“…Published on August 24, 2020 as DOI: 10.1124/dmd.120.000092 at ASPET Journals on May 2, 2021 dmd.aspetjournals.org Downloaded from concentration in the phagocytes is achieved when dmDNA31 is conjugated to anti-S. aureus antibody due to target engagement and the subsequent antibody opsonization. In previous studies, the systemic pharmacokinetics (PK) and pharmacodynamics (PD) of TAC were evaluated in different preclinical models (Deng et al, 2019). Single administration of TAC significantly reduced the bacterial load in kidney and heart from SCID mice infected with S. aureus bacteria (Zhou et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Tissue Distribution, Catabolism, and Elimination of an Anti–Staphylococcus aureusTHIOMAB Antibody-Antibiotic Conjugate in Rats

Cai¹,

Yip²,

Lee³

et al. 2020

Drug Metab Dispos

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Invasive Staphylococcus aureus (S. aureus) infection is a leading cause of infectious diseaserelated deaths due to the survival of S. aureus within host phagocytic cells, by which the bacteria are not adequately eliminated using current antibiotic treatments. Anti-S. aureus THIOMAB TM antibody-antibiotic conjugate (TAC), an anti-S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus. Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC, as well as the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches.Intravenous injection of unconjugated [ 14 C]-dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [ 14 C]-dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites.In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection.

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Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate againstStaphylococcus aureus

Cited by 28 publications

References 35 publications

Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance

Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

Characterization of Tissue Distribution, Catabolism, and Elimination of an Anti–Staphylococcus aureusTHIOMAB Antibody-Antibiotic Conjugate in Rats

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