Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cαStx2 Administered Intravenously to Healthy Adult Volunteers

Dowling, Thomas C.; Chavaillaz, Pierre A.; Young, David W.; Melton‐Celsa, Angela R.; O'Brien, Alison D.; Thuning-Roberson, Claire; Edelman, Robert; Tacket, Carol O.

doi:10.1128/aac.49.5.1808-1812.2005

Cited by 68 publications

(53 citation statements)

References 10 publications

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“…Headache was the most common event reported. The development of human anti-mAb antibodies was reported as undetected for tefibazumab, 19 but 4 of 17 subjects (24%) dosed with caStx2 developed HACA, 18 though like the anti-chmAb7F9 reported here, the response was not dose related.…”

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 72%

“…17,19 Pagibaximab is somewhat longer at 33 days 20 and caStx2 is shorter at 8.6 d 18 The long ch-mAb7F9 elimination half-life could be a substantial improvement over many small molecule medications used to treat METH users. Because of its 18-day half-life, ch-mAb7F9 dosing should be no more frequent than every 3 weeks, which will increase compliance for motivated patients.…”

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

“…16,17 The chimeric IgG1k, caStx2, which binds a subunit of the E. coli protein Stx2, has been administered at 10 mg/kg. 18 Two mAbs intended to treat sepsis from staphylococci are the humanized IgG1k tebifazumab, 19 which binds clumping factor A and the chimeric IgG1 pagibaximab, 20 which binds lipoteichoic acid. Both have been dosed in healthy subjects up to 20 and 10 mg/kg, respectively.…”

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

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First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Stevens

Henry

Owens

et al. 2014

mAbs

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This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

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Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 72%

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

See 1 more Smart Citation

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Stevens

Henry

Owens

et al. 2014

mAbs

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“…In addition, we observed that the OIA method was more sensitive than the EIA (14). In addition, therapies such as humanized monoclonal antibodies that can be passively administered to protect against Shiga toxins are in development (5,13). Once these therapies are available, at-risk patients who have been identified by rapid toxin detection methods can be treated promptly, since the efficacy of such interventions is likely to be proportional to the speed with which therapy is administered.…”

Section: Discussionmentioning

confidence: 96%

Rapid Detection of Shiga Toxin-Producing Escherichia coli by Optical Immunoassay

et al. 2007

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In a multi-health center study, a new rapid optical immunoassay (OIA) for the detection of Shiga toxin types 1 and 2, the BioStar OIA SHIGATOX kit (Inverness Medical Professional Diagnostics, Inc.), was used to prospectively screen 742 fresh fecal samples for Shiga toxins in parallel with the Premier enterohemorrhagic Escherichia coli (EHEC) kit (Meridian BioScience, Inc.) with and without enrichment of the specimens by incubation in MacConkey broth. Additionally, 85 previously tested frozen fecal samples were assessed as described above. All positive immunoassay results were confirmed by the Vero cell cytotoxicity assay. A further modification of the screening procedure was evaluated on 470 of the prospectively screened specimens. Swabs of growth from conventionally plated stool culture media were subjected to the OIA SHIGATOX, and results were compared with those obtained with the Premier EHEC kit following broth enrichment. Overall, the OIA SHIGATOX kit was significantly more sensitive than the Premier EHEC kit on fresh direct stool specimens (sensitivities, 96.8% and 83.9%, respectively; P < 0.05). The two assays performed equally well with each other on frozen and broth-enriched samples. The colony sweep method used in conjunction with the OIA kit was somewhat more effective at detection of Shiga toxins from growth on agar than the overnight broth enrichment procedure used with the Premier EHEC assay (sensitivities, 100% and 92%, respectively; P < 0.09). Overall, the OIA SHIGATOX kit provided rapid, easy-to-interpret results and was highly effective at detection of Shiga toxin-producing E. coli in fecal samples and overnight cultures.

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“…72 Many therapeutic Abs demonstrate rapid clearance when their serum concentrations fall below a threshold concentration, corresponding to the point of equal amounts of Ab and target. [73][74][75] Volumes of distribution After intravenous administration, mAbs initially distribute into a volume roughly equal to the plasma volume (0.045 L/kg) 3,73,76 and on approaching steady state the volume of distribution increases to approximately 0.1 L/kg, reflecting only limited extravascular distribution. [77][78][79] Biodistribution studies in animals lacking the target Ag have shown that the largest percentage of the dose of mAb is in the plasma and that whole-body distribution predominantly targets organs that are highly perfused with blood.…”

Section: Pharmacokinetic Considerations Systemic Clearancementioning

confidence: 99%

Antibody constructs in cancer therapy

Beckman

Weiner

Davis³

2007

Cancer

250

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Whereas over 85% of human cancers are solid tumors, of the 8 monoclonal antibodies (mAbs) currently approved for cancer therapy, 25% are directed at solid tumor surface antigens (Ags). This shortfall may be due to barriers to achieving adequate exposure in solid tumors. Advancements in tumor biology, protein engineering, and theoretical modeling of macromolecular transport are currently enabling identification of critical physical properties for antitumor Abs. It is now possible to structurally modify Abs or even replace full Abs with a plethora of Ab constructs. These constructs include Fab and Fab 0 2 fragments, scFvs, multivalent scFvs (e.g., diabodies and tribodies), minibodies (e.g., scFv-CH3 dimers), bispecific Abs, and camel variable functional heavy chain domains. The purpose of the article is to provide investigators with a conceptual framework for exploiting the recent scientific advancements. The focus is on 2 properties that govern tumor exposure: 1) physical properties that enable penetration of and retention by tumors, and 2) favorable plasma pharmacokinetics. It is demonstrated that manipulating molecular size, charge, valence, and binding affinity can optimize these properties.These manipulations hold the key to promoting tumor exposure and to ultimately creating successful Ab therapies for solid tumors.

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Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cαStx2 Administered Intravenously to Healthy Adult Volunteers

Abstract: Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing

Cited by 68 publications

References 10 publications

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Rapid Detection of Shiga Toxin-Producing Escherichia coli by Optical Immunoassay

Antibody constructs in cancer therapy

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