Future Perspectives of Therapeutic Monoclonal Antibodies

Tsumoto, K.; Isozaki, Yushi; Yagami, Hisanori; Tomita, Masahiro

doi:10.2217/imt-2018-0130

Cited by 97 publications

(61 citation statements)

References 27 publications

(27 reference statements)

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“…Antibody-based molecules have become an essential component of cancer treatment (Tsumoto et al, 2019); however, limited distribution to the site of action has greatly limited the efficacy of antibodies for solid tumors. Several molecular and physicochemical properties govern the disposition of antibody-based molecules in the tumor, of which molecular size is probably the most important and most extensively studied property.…”

Section: Discussionmentioning

confidence: 99%

Effect of Size on Solid Tumor Disposition of Protein Therapeutics

Chang

et al. 2019

Drug Metab Dispos

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In this study, we evaluated the effect of size on tumor disposition of protein therapeutics, including the plasma and tumor pharmacokinetics (PK) of trastuzumab (∼150 kDa), FcRn-nonbinding trastuzumab (∼150 kDa), F(ab) 2 fragment of trastuzumab (∼100 kDa), Fab fragment of trastuzumab (∼50 kDa), and trastuzumab scFv (∼27 kDa) in both antigen (i.e., HER2)-overexpressing (N87) and antigennonexpressing (MDA-MB-468) tumor-bearing mice. The observed data were used to develop the maximum tumor uptake versus molecular weight and tumor-to-plasma area under the curve (AUC) ratio versus molecular weight relationships. Comparison of the PK of different sizes of FcRn nonbinding molecules in target-expressing tumor showed that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio of protein therapeutics. The PK data were also used to validate a systems PK model for tumor disposition of different-sized protein therapeutics. The PK model was able to predict a priori the PK of all five molecules in both tumor types reasonably well (within 2-to 3-fold). In addition, the model captured the bell-shaped relationships observed between maximum tumor uptake and molecular weight and between tumor-to-plasma AUC ratio and molecular weight. Our results provide an unprecedented insight into the effect of size and target engagement on the tumor PK of protein therapeutics. Our results also provide further validation of the tumor disposition model, which can be used to support discovery, development, and preclinical-to-clinical translation of different sizes of protein therapeutics. SIGNIFICANCE STATEMENT This article highlights the importance of molecular size and target engagement on the tumor disposition of protein therapeutics. Our results suggest that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio for non-FcRn-binding targeted protein therapeutics. We also demonstrate that a systems pharmacokinetics model developed to characterize tumor disposition of protein therapeutics can predict a priori the disposition of different-sized protein therapeutics in target-expressing and targetnonexpressing solid tumors.

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Section: Discussionmentioning

confidence: 99%

Effect of Size on Solid Tumor Disposition of Protein Therapeutics

Chang

et al. 2019

Drug Metab Dispos

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“…By definition, monoclonal antibodies (Mab) are a protein secreted by specific white blood cells of the animal or human origin which have the ability to recognize specific targets called antigens (15). As of 2018, a total of 64 therapeutic antibodies were approved by the FDA; 18 were approved by either the US or the EU in 2017, and 4 in have been approved or are under review in 2019 (16,17). In fact, therapeutic antibody approvals and commercialization are flourishing with 570 antibodies currently in clinical trials (18).…”

Section: The Potential Of Antibodies In Targeted Therapymentioning

confidence: 99%

The potential of Fluorine 19F in in Targeted Therapy

Bartusik‐Aebisher¹,

Aebisher²,

Podgórski³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Fluorine-19 (19 F) can provide critical information about drug uptake in cancer tissue when used together with 19 F Magnetic Resonance Imaging (19 F MRI) in vitro or in vivo. This review is aimed at the current limitations of drugs such as quantitative visualization during treatments of tumor cells. The main rationale for the utility of 19 F MRI is the visualization of fluorinated drug and fluorine conjugates at the cellular in vitro and in vivo levels.

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“…Monoclonal antibodies (mAbs) have attracted increasing attention as the most rapidly growing drug class towards diseases such as cancer, autoimmune disorders, and chronic inflammatory diseases due to their high specificity and affinity for targeted antigens [ [1] , [2] , [3] ]. Soon after Köhler et al.…”

Section: Introductionmentioning

confidence: 99%

“…[ 4 ] fused B cells with myeloma cells to facilitate the efficient production of mAbs in 1975, the world’s first mAb drug OKT3 (Muromonab-CD3) was approved by the US Food and Drug Administration (FDA) in 1985, followed by the launch of the first fully human mAb, Adalimumab, attributing to the breakthrough of phage display technology in 2002 [ 5 ]. Therapeutic mAbs entered a rapid development stage since then, with a total number of 64 approved mAbs by the US FDA in 2018 [ 3 ] and 5 novel antibody therapeutics have been granted the first approval as of November 2019 with 79 more undergoing evaluations in late-stage clinical studies [ 6 ]. With improvements in genetic engineering and conjugation strategies, therapeutic mAbs have expanded from full-length immunoglobulin G (IgG) containing double heavy and light chains to derivatives like single-chain antibody (ScFv), nanobody, affibody, bispecific antibody, etc.…”

Section: Introductionmentioning

confidence: 99%

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

Zeng

Qian

2020

Journal of Pharmaceutical Analysis

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Therapeutic monoclonal antibodies have become one of the central components of the healthcare system and continuous efforts are made to bring innovative antibody therapeutics to patients in need. It is equally critical to acquire sufficient knowledge of their molecular structure and biological functions to ensure the efficacy and safety by incorporating new detection approaches since new challenges like individual differences and resistance are presented. Conventional techniques for determining antibody disposition including plasma drug concentration measurements using LC-MS or ELISA, and tissue distribution using immunohistochemistry and immunofluorescence are now complemented with molecular imaging modalities like positron emission tomography and near-infrared fluorescence imaging to obtain more dynamic information, while methods for characterization of antibody’s interaction with the target antigen as well as visualization of its cellular and intercellular behavior are still under development. Recent progress in detecting therapeutic antibodies, in particular, the development of methods suitable for illustrating the molecular dynamics, is described here.

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Future Perspectives of Therapeutic Monoclonal Antibodies

Cited by 97 publications

References 27 publications

Effect of Size on Solid Tumor Disposition of Protein Therapeutics

Effect of Size on Solid Tumor Disposition of Protein Therapeutics

The potential of Fluorine 19F in in Targeted Therapy

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

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