Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers

Paci, Angélo; Desnoyer, Aude; Delahousse, J; Blondel, Louis; Maritaz, Christophe; Chaput, Nathalie; Mir, Olivier; Broutin, Sophie

doi:10.1016/j.ejca.2020.01.005

Cited by 46 publications

(30 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…45 Both absorption and metabolism phases are almost non-existent; their distribution is mainly in the blood and extracellular fluids due to their size and hydrophilicity, while elimination occurs by intracellular degradation subsequent to their Fc receptor binding and target recognition specificities and, less frequently, by proteolytic catabolism. 46 The binding of mAbs to the target at the cell surface depends on tumor burden, expression levels of target and mAb affinity, while it is not affected by body weight. Conversely, proteolytic catabolism of mAbs targeting soluble targets taking place in endosomal space (accounting for 0.5% of the total tissue volume) is body-weight dependent, although its impact on total drug elimination is slight.…”

Section: Eliminationmentioning

confidence: 99%

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper

et al. 2021

View full text Add to dashboard Cite

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.

show abstract

Section: Eliminationmentioning

confidence: 99%

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These two factors, combined with FcRn-mediated recycling, result in the prolonged half-life of mAbs. PK properties of mAb-based therapeutics can vary based on their nature (humanized vs. human), type (IgG1, 2, 3, or 4) and mode of binding (monospecific vs. multispecific) [ 215 ]. Systematically administered mAbs generally show biphasic PK profiles, characterized by a fast distribution phase followed by a slower elimination phase [ 214 ].…”

Section: Polyspecificty and In Vivo Propertiesmentioning

confidence: 99%

Toward Drug-Like Multispecific Antibodies by Design

Sawant

Streu

et al. 2020

IJMS

View full text Add to dashboard Cite

The success of antibody therapeutics is strongly influenced by their multifunctional nature that couples antigen recognition mediated by their variable regions with effector functions and half-life extension mediated by a subset of their constant regions. Nevertheless, the monospecific IgG format is not optimal for many therapeutic applications, and this has led to the design of a vast number of unique multispecific antibody formats that enable targeting of multiple antigens or multiple epitopes on the same antigen. Despite the diversity of these formats, a common challenge in generating multispecific antibodies is that they display suboptimal physical and chemical properties relative to conventional IgGs and are more difficult to develop into therapeutics. Here we review advances in the design and engineering of multispecific antibodies with drug-like properties, including favorable stability, solubility, viscosity, specificity and pharmacokinetic properties. We also highlight emerging experimental and computational methods for improving the next generation of multispecific antibodies, as well as their constituent antibody fragments, with natural IgG-like properties. Finally, we identify several outstanding challenges that need to be addressed to increase the success of multispecific antibodies in the clinic.

show abstract

“…The ADC was also shown to be well tolerated. 42 Furthermore, FDA approved Mylotarg again in 2017 as an orphan drug for the treatment of CD33-positive acute myeloid leukemia, after Pfizer revised the dosing regimen and confirmed the efficacy, which out-weighs the harmful effects. 43 With the aim of further improving the hydrazone linker, Zheng et al developed a safety-catch strategy by combining an acyl hydrazone linker with a proteolytic bridge to form a peptide-bridged twin-acylhydrazone (PTA) linker ( Figure 3).…”

Section: Imine/hydrazone/oxime Linkersmentioning

confidence: 99%

“…As a matter of fact, a CD22‐targeting ADC, inotuzumab ozogamicin (Besponsa®, launched in 2017), utilizes the same hybridized AcBut‐acylhydrazone linker, which led to a half‐life of 12.3 days, demonstrating stability. The ADC was also shown to be well tolerated 42 . Furthermore, FDA approved Mylotarg again in 2017 as an orphan drug for the treatment of CD33‐positive acute myeloid leukemia, after Pfizer revised the dosing regimen and confirmed the efficacy, which out‐weighs the harmful effects 43 …”

Section: Ph‐sensitive Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

View full text Add to dashboard Cite

Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

show abstract

Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers

Cited by 46 publications

References 65 publications

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper

Toward Drug-Like Multispecific Antibodies by Design

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Contact Info

Product

Resources

About