Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Thomas, Veena A.; Balthasar, Joseph P.

doi:10.3390/antib8040056

Cited by 58 publications

(57 citation statements)

References 383 publications

(421 reference statements)

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“…The IgG antibody class has been used almost exclusively for RPT. IgG antibodies are proteins with a molecular weight of 150,000 and which have a long biological half-life in the circulation (2–5 days, depending on their isotype and structure) and are eventually catabolized by the liver and elements of the reticuloendothelial system 213 , 214 . The ability to generate antibodies possessing well-defined reactivity characteristics against selected antigens (that is, monoclonal antibodies 215 ) was a precondition for the use of antibodies as viable radionuclide delivery vehicles.…”

Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

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Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.

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Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

View full text Add to dashboard Cite

show abstract

“…Covariates were selected based on their potential clinical relevance. The possible physiological basis for commonly evaluated covariates such as body size, age, gender, race, ADA, serum albumin, creatinine clearance, etc., were summarized by Thomas and Balthasar [23]. Selection of the final…”

Section: Human Population Pharmacokinetic Analysismentioning

confidence: 99%

Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial

Xiang

Liu²,

Gao³

et al. 2020

Cancer Chemother Pharmacol

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Purpose To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. Methods Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma. Results Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. Conclusion A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

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“…Indeed, the individual pharmacodynamic properties of mAbs are specific to the biology of their target antigen but also directly impact the pharmacokinetic characteristics. Binding to the target antigen, internalization, related intracellular protein catabolism and Fc-mediated effects do not only participate in the mechanism of action of mAbs, but may influence their clearance and those of potential combined agents too [52,64]. This underscores the need to evaluate the pharmacokinetics of each therapeutic mAb used for the treatment of MM, but also the need to repeat the process for any new therapeutic combination [65,66].…”

Section: So What?mentioning

confidence: 99%

ImmunoPET in Multiple Myeloma—What? So What? Now What?

Bailly

Chalopin

Gouard

et al. 2020

Cancers

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Despite constant progress over the past three decades, multiple myeloma (MM) is still an incurable disease, and the identification of new biomarkers to better select patients and adapt therapy is more relevant than ever. Recently, the introduction of therapeutic monoclonal antibodies (mAbs) (including direct-targeting mAbs and immune checkpoint inhibitors) appears to have changed the paradigm of MM management, emphasizing the opportunity to cure MM patients through an immunotherapeutic approach. In this context, immuno-positron emission tomography (immunoPET), combining the high sensitivity and resolution of a PET camera with the specificity of a radiolabelled mAb, holds the capability to cement this new treatment paradigm for MM patients. It has the potential to non-invasively monitor the distribution of therapeutic antibodies or directly monitor biomarkers on MM cells, and to allow direct observation of potential changes over time and in response to various therapeutic interventions. Tumor response could, in the future, be anticipated more effectively to provide individualized treatment plans tailored to patients according to their unique imaging signatures. This work explores the important role played by immunotherapeutics in the management of MM, and focuses on some of the challenges for this drug class and the significant interest of companion imaging agents such as immunoPET.

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Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Cited by 58 publications

References 383 publications

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial

ImmunoPET in Multiple Myeloma—What? So What? Now What?

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