Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik, Meric; Lin, Kedan

doi:10.1111/cts.12567

Cited by 207 publications

(181 citation statements)

References 96 publications

(183 reference statements)

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“…46 Compared to small molecules, mAbs have a very long half-life in circulation, typically 11-30 days in humans, and thus require much lower dosing frequencies. 42 The IgG Fc region has a recognition domain for the neonatal Fc Receptor (FcRn), which is constitutively expressed in the vascular endothelium and recycles IgG by receptor-mediated endocytosis. This protects IgG from lysosomal degradation and allows its trafficking and release back into the circulation, thus increasing its half-life.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Optimization of these factors can be done to improve the distribution of mAbs to target organs. 42 mAb distribution can be studied using physiologically based pharmacokinetic modeling to describe the process of convection as a product of the lymph flow rate and an efficiency term, as well as integrated analytical tools. 13 Examples of successful PK/PD modeling where preclinical data can be used to project the human efficacious dose have been reported.…”

Section: Pharmacokineticsmentioning

confidence: 99%

See 1 more Smart Citation

The pharmacology and therapeutic applications of monoclonal antibodies

Castelli

McGonigle

Hornby

2019

Pharmacology Res & Perspec

209

111

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Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane‐bound receptors and have increased circulating half‐life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off‐target effects and drug‐drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off‐target adverse effects, fewer drug‐drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

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Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

The pharmacology and therapeutic applications of monoclonal antibodies

Castelli

McGonigle

Hornby

2019

Pharmacology Res & Perspec

209

111

View full text Add to dashboard Cite

show abstract

“…Monoclonal antibodies typically exhibit slow systemic clearance and low volume of distribution (Vd) as their size and polarity confines their distribution to the vascular and interstitial spaces [ 199 , 214 ]. These two factors, combined with FcRn-mediated recycling, result in the prolonged half-life of mAbs.…”

Section: Polyspecificty and In Vivo Propertiesmentioning

confidence: 99%

Toward Drug-Like Multispecific Antibodies by Design

Sawant

Streu

et al. 2020

IJMS

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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.

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“…Early PK liabilities of mAb drugs were often usually identified using rodent models. Pilot PK/PD and safety studies are in appropriate species (NHP and rodent) [18]. So we evaluated the PK of TA1718-B using rats, mice and monkeys.…”

Section: The Excretion Of 125 I-ta1718-b In Ratsmentioning

confidence: 99%

Preclinical Elucidation of Recombinant Humanized Anti-PD-1 Monoclonal Antibody (TA1718-B) Pharmacokinetics in Cynomolgus Monkeys, Rats, and Colon Cancer Humanized Mice

Zhao¹,

Lv²,

Li³

et al. 2019

Preprint

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[EXSCINDED] Abstract Background PD-1 monoclonal antibodies (mAbs) are widely applicated in clinical as therapeutic strategy for multiple types of cancer. TA1718-B, a novel PD-1 mAb, is now entering clinical phase I.Methods In present study, the preclinical pharmacokinetic (PK) properties of TA1718-B were investigatedviavarious experiments in animal species. In plasma kinetic studies, cynomolgus monkeys underwent either single (1, 3, and 10 mg/kg) or repeat (4-times, 3 mg/kg) intravenous injection and plasma were collected in different time points and detected by ELISA. Tissue distributions were performed in MC38 colon cancer humanizedmice. The excretion of TA1718-B was evaluated in rats.Results TA1718-B exhibited long T1/2 (from 97 to 136 hrs) and low clearance (Cl) (from 0.25 to 0.38 ml/h/kg) after intravenous single injection in cynomolgus monkeys. And 4-time continuous injections were not resulted in significant drug accumulation. However, both two drug delivery ways resulted in high anti-drug antibody (ADA) positive rates. The tissue distributions of TA1718-B were widely (almost in all tissues) and higher in serum, ovary, lung, tumorthan the other tissues in MC38 colon cancer humanized mice. The excretion of TA1718-B in rats were mainly metabolized and eliminated through proteolytic degradation.Radiopharmaceuticals in urine mainly existed in the form of proteolytic degradationfrom the data.Conclusion This systematic investigation of pharmacokinetic profiles of TA1718-B supplies basis for clinical trials and need to be further studied in Phase I clinical trial.

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Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Cited by 207 publications

References 96 publications

The pharmacology and therapeutic applications of monoclonal antibodies

The pharmacology and therapeutic applications of monoclonal antibodies

Toward Drug-Like Multispecific Antibodies by Design

Preclinical Elucidation of Recombinant Humanized Anti-PD-1 Monoclonal Antibody (TA1718-B) Pharmacokinetics in Cynomolgus Monkeys, Rats, and Colon Cancer Humanized Mice

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