The biodistribution of therapeutic proteins: Mechanism, implications for pharmacokinetics, and methods of evaluation

Conner, Kip P.; Devanaboyina, Siva Charan; Thomas, Veena A.; Rock, Dan A.

doi:10.1016/j.pharmthera.2020.107574

Cited by 21 publications

(30 citation statements)

References 248 publications

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“…While the role of extravasation in the tissue uptake of large molecules is well-known [2,8], we were interested whether in vivo differences in tissue uptake can be mirrored in the in vitro model. In this case, such an in vitro model would deserve further characterization in order to use it in the long run as replacement for tissue uptake studies in animals.…”

Section: Discussionmentioning

confidence: 99%

“…Monoclonal antibodies have gained tremendous importance in the treatment of a wide range of diseases over the last two decades [1]. The distinctive combination of high target binding affinity, exquisite specificity, and extraordinarily long plasma half-lives have been pivotal to their clinical success [2]. The exceptional plasma residence time is afforded by salvage mediated through the neonatal Fc receptor (FcRn), which protects antibodies from rapid lysosomal degradation [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…The distinctive combination of high target binding affinity, exquisite specificity, and extraordinarily long plasma half-lives have been pivotal to their clinical success [2]. The exceptional plasma residence time is afforded by salvage mediated through the neonatal Fc receptor (FcRn), which protects antibodies from rapid lysosomal degradation [2,3]. The FcRn interaction also affects biodistribution and tissue catabolism of antibodies [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Impact of charge patches on tumor disposition and biodistribution of therapeutic antibodies

Stueber

Miladinović

Pöschinger

et al. 2021

Preprint

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This study explores the impact of antibody surface charge on tissue distribution into various tissues including tumor. Tumor-bearing mice were dosed intravenously with a mixture of three antibodies engineered to carry negative charge patches, a balanced charge distribution, or positive patches, respectively. Tissue levels were analyzed with a specific LC-MS/MS method. In addition, the antibody mix was administered to non-tumor bearing mice. Muscle and skin interstitial fluid were obtained by centrifugation and analyzed by LC-MS/MS. An in-vitro endothelium model was explored for its feasibility to mimic the observed distribution differences. A balanced charge distribution was optimal in terms of total tumor exposure, while in other tissues negatively charged and balanced charged antibodies gave similar results. In contrast, positive charge patches generally result in increased serum clearance but markedly enhance tumor and organ uptake, leading to higher tissue-to-serum ratios. The uptake and availability in the interstitial space were confirmed by specific assessment of antibody levels in the interstitial fluid of muscle and skin, with similar charge impact as in total tissue. The in vitro model was able to differentiate the transport propensity of this series of antibody variants. In summary, our results show the differential effects of charge patches on an antibody surface on biodistribution and tumor uptake. These insights may help in the design of molecules with biodistribution properties tailored to their purpose and an optimized safety profile.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of charge patches on tumor disposition and biodistribution of therapeutic antibodies

Stueber

Miladinović

Pöschinger

et al. 2021

Preprint

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“…The PK properties of therapeutic antibodies are an essential factor that determine their in vivo efficacy by impacting their biodistribution and have been extensively studied in recent years [ 20 ]. The processes that govern the biodistribution of therapeutic antibodies depends on the species they are administered to and on the properties of the antibody itself.…”

Section: Delivery Of Antibodies Into the Brain: Mechanism Of Deliverymentioning

confidence: 99%

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Kouhi

Pachipulusu

Kapenstein

et al. 2021

IJMS

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Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.

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“…However, for antibodies with distal targets, their exposures at the site of actions are usually hard to characterize, obscuring exposure-response relationships. Evaluating antibody exposure at target sites is thus a critical task in antibody development and evaluation [85,86]. This section will introduce state-of-the-art tools for assessing antibody distribution in tissues and modeling antibody distribution determinants.…”

Section: Assessing Antibody Low Tissue Distributionmentioning

confidence: 99%

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

Tang

Cao

2021

Pharmaceutics

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With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing many therapeutic advantages such as long half-life and highly selective actions, therapeutic antibodies still face many outstanding issues associated with their pharmacokinetics (PK) and pharmacodynamics (PD), including high variabilities, low tissue distributions, poorly-defined PK/PD characteristics for novel antibody formats, and high rates of treatment resistance. We have witnessed many successful cases applying PK/PD modeling to answer critical questions in therapeutic antibodies’ development and regulations. These models have yielded substantial insights into antibody PK/PD properties. This review summarized the progress, challenges, and future directions in modeling antibody PK/PD and highlighted the potential of applying mechanistic models addressing the development questions.

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The biodistribution of therapeutic proteins: Mechanism, implications for pharmacokinetics, and methods of evaluation

Cited by 21 publications

References 248 publications

Impact of charge patches on tumor disposition and biodistribution of therapeutic antibodies

Impact of charge patches on tumor disposition and biodistribution of therapeutic antibodies

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

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