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Cited by 299Monoclonal and Polyclonal Antibodies ResearchBiosimilars and Bioanalytical MethodsImmunotoxicology and immune responses

Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development

Open access
Ovacik, Meric, Lin, Kedan·2018·Clinical and Translational Science
DOI 10.1111/cts.12567PMC PMC6226118
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Abstract

The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision‐making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies.

AI snapshot

Written from the paper’s full text.

TL;DR

This tutorial reviews monoclonal antibody pharmacokinetics, including absorption, distribution, catabolism, target-mediated clearance, immunogenicity, and translational PK/PD considerations in early development. It emphasizes that mAb PK is driven by interactions with antigen, FcγRs, and FcRn, and that PK/PD modeling supports lead selection, preclinical species choice, human PK projection, and first-in-human dose selection.

Key findings

  • Systemically administered mAbs typically show biphasic PK, confined distribution to vascular/interstitial space, long half-lives of ∼11–30 days in humans from FcRn-mediated recycling, and nonlinear PK due to target-mediated clearance.
  • Marketed mAbs exhibit clearance values between 90–560 mL/day and half-lives between 11–30 days, comparable to endogenous IgG half-life (∼21 days); volume of distribution is generally 3–8 L at steady state.
  • Subcutaneous bioavailability varies between 50–90% with maximum plasma concentrations often reached around 3–7 days postdosing, whereas oral bioavailability is typically <1–2%.
  • In a survey of recently approved mAbs, immunogenicity incidence rates varied from 0% to as high as 42%; ADA formation may accelerate mAb clearance and affect exposure, efficacy, and safety.

Methods

  • Design: narrative tutorial/review introducing fundamentals of antibody PK and its application in early drug development decision-making.
  • Data or sample: synthesizes published literature and tabulates PK parameters for marketed mAbs (2011–2017) as indicated in their labels; notes over 60 marketed antibodies in the United States and ∼350 new antibody entities in active clinical development.
  • Main analysis: narrative synthesis of mAb-specific PK concepts, comparison tables between small molecules and mAbs, and discussion of preclinical/clinical PK/PD translation; no primary experimental study or meta-analysis is reported.

Limitations

  • The paper states no formal limitations section.
  • Evident from the text: this is a tutorial/narrative review rather than a systematic review or primary investigation, so it does not provide new experimental data or quantitative synthesis.
  • Evident from the text: Table 3 contains blank cells and notes some values are not reported (e.g., daratumumab immunogenicity not reported due to assay interference); the paper also states that immunogenicity in preclinical species cannot predict the incidence of human ADAs.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/cts.12567

Cites

96 of 96 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 106 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    From a survey of recently approved mAbs, immunogenicity incidence rates varied from 0% to as high as 42%.

    “From a survey of recently approved mAbs, immunogenicity incidence rates varied from 0% to as high as 42% (Table 3).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Marketed antibodies often show relatively narrow ranges of PK parameters.

    “Marketed antibodies often show relatively narrow ranges of PK parameters (Table 3).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Alemtuzumab, an antibody targeting CD52-expressing tumor cells, showed time-dependent PK with decreased clearance and extended half-life as tumor burden decreases after repeated dosing.

    “For example, alemtuzumab, an antibody targeting CD52‐expressing tumor cells, showed time‐dependent PK with decreased clearance and extended half‐life as tumor burden decreases after repeated dosing.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Mould, D.R. et al Population pharmacokinetics‐pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response. Br. J. Clin. Pharmacol. 64, 278– 291 (2007). 17506867 PMC2000651 source

      Not checked in the free run.

  • Premisecitation

    Factors influencing mAbs distribution to individual organs or tissues include drug-specific features such as binding affinity to target antigens, target internalization rate, mAb hydrophilicity, and charge, and tissue-specific features such as membrane structure and blood flow.

    “Additional factors influencing mAbs distribution to individual organs or tissues include: drug‐specific features such as their binding affinity to specific target antigens, targets internalization rate,24 mAb hydrophilicity, charge,25 and tissue‐specific features such as membrane structure and blood flow.26”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Rudnick, S.I. & Adams, G.P. Affinity and avidity in antibody‐based tumor targeting. Cancer Biother. Radiopharm. 24, 155– 161 (2009). 19409036 PMC2902227 source

      Not checked in the free run.

    • cites [25] Boswell, C.A., Tesar, D.B., Mukhyala, K., Theil, F.P., Fielder, P.J. & Khawli, L.A. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug. Chem. 21, 2153– 2163 (2010). 21053952 source

      Not checked in the free run.

    • cites [26] Deng, R., Jin, F., Prabhu, S. & Iyer, S. Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development? Expert Opin. Drug Metab. Toxicol. 8, 141– 160 (2012). 22248267 source

      Not checked in the free run.

  • Premisecitation

    Non-human primate models are often used for early assessment of bioavailability because of their physiological and biochemical proximity to humans.

    “Non‐human primate (NHP) models are often used for early assessment of bioavailability for their physiological and biochemical proximity to humans.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Datta‐Mannan, A., Witcher, D.R., Lu, J. & Wroblewski, V.J. Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys. MAbs. 4, 267– 273 (2012). 22377715 PMC3361662 source

      Not checked in the free run.

  • May combine two claims. 23
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingnone given

    The maximum plasma concentrations of mAbs are often reached around 3-7 days postdosing, and bioavailability varies between 50-90% following s.c. dosing in humans.

    “The maximum plasma concentrations of mAbs are often reached around 3–7 days postdosing and bioavailability varies between 50–90% following s.c. dosing in humans (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    mAbs have limited oral bioavailability, typically less than 1-2%, and are therefore not usually administered orally.

    “mAbs have limited oral bioavailability (typically <1–2%)15 and are therefore not usually administered orally.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Renukuntla, J., Vadlapudi, A.D., Patel, A., Boddu, S.H. & Mitra, A.K. Approaches for enhancing oral bioavailability of peptides and proteins. Int. J. Pharm. 447, 75– 93 (2013). 23428883 PMC3680128 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The limited bioavailability of orally administered mAbs is due to limited penetration across the intestinal epithelium and susceptibility to enzymatic degradation by proteases and peptidases in the intestinal lumen.

    “The limited bioavailability of orally administered mAbs is due to their limited penetration across the intestinal epithelium16 and susceptibility to enzymatic degradation by proteases and peptidases in the intestinal lumen.17”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Morishita, M. & Peppas, N.A. Is the oral route possible for peptide and protein drug delivery? Drug Discov. Today. 11, 905– 910 (2006). 16997140 source

      Not checked in the free run.

    • cites [17] Singh, R., Singh, S. & Lillard, J.W., Jr. Past, present, and future technologies for oral delivery of therapeutic proteins. J. Pharm. Sci. 97, 2497– 2523 (2008). 17918721 PMC4627499 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rudnick et al. showed that when targeting high-density and rapidly internalized antigens such as HER2, a lower-affinity antibody could penetrate tumors more effectively, while an ultrahigh-affinity antibody could limit the distribution of the antibody to tumor as a result of binding site barrier.

    “For example, Rudnick et al. showed that when targeting high‐density and rapidly internalized antigens such as HER2, a lower‐affinity antibody could penetrate tumors more effectively, while an ultrahigh‐affinity antibody could limit the distribution of the antibody to tumor as a result of “binding site barrier.”27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Rudnick, S.I. et al Influence of affinity and antigen internalization on the uptake and penetration of Anti‐HER2 antibodies in solid tumors. Cancer Res. 71, 2250– 2259 (2011). 21406401 PMC3077882 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Yadav et al. demonstrated that modifying Fv charge and hydrophobicity altered mAb PK and s.c. bioavailability; more positive-charged antibody variants showed faster nonspecific clearance than the less positively charged variants or the wildtype.

    “Yadav et al. also demonstrated that modifying Fv charge and hydrophobicity altered mAb PK and s.c. bioavailability42: more positive‐charged antibody variants showed faster nonspecific clearance than the less positively charged variants or the wildtype.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bumbaca Yadav, D. et al Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics. J. Biol. Chem. 290, 29732– 29741 (2015). 26491012 PMC4705991 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The FcRn-mediated recycling process is most likely responsible for the observed relatively long half-life of mAbs of 11-30 days in humans, which is similar to the half-life of endogenous IgG (~21 days).

    “This recycling process is most likely responsible for the observed relatively long half‐life of mAbs of 11–30 days in humans (Table 3), which is similar to the half‐life of endogenous IgG (∼21 days).31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Dirks, N.L. & Meibohm, B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49, 633– 659 (2010). 20818831 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gibbs et al. demonstrated the critical importance of characterizing target-mediated clearance in selecting an optimal dosing regimen for the PCSK9 antibody evolocumab; their TMDD PK/PD modeling suggested that doubling the dose and extending the dosing interval from biweekly to monthly did not adequately maintain the reduction in LDL-C, and a higher dose was required to maintain stable LDL-C levels

    “For example, Gibbs et al. demonstrated the critical importance of characterizing target‐mediated clearance in selecting an optimal dosing regimen for protein convertase substilisin kexin type 9 (PCSK9) antibody evolucumab.37 Their target‐mediated drug disposition PK/PD modeling suggested that doubling the dose and extending the dosing interval from biweekly to monthly did not adequately maintain”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Gibbs, J.P. et al Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). J. Clin. Pharmacol. 57, 616– 626 (2017). 27861991 PMC5412926 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Target-mediated clearance refers to the elimination of mAbs through antigen-specific interactions; after mAbs bind a specific antigen, they may be internalized and catabolized through lysosomal degradation as an antibody-antigen complex.

    “Target‐mediated clearance refers to the elimination of mAbs through its antigen‐specific interactions. After mAbs bind to a specific antigen (soluble or membrane bound) they may be internalized and catabolized through lysosomal degradation as an antibody–antigen complex.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Mellman, I. & Plutner, H. Internalization and degradation of macrophage Fc receptors bound to polyvalent immune complexes. J. Cell Biol. 98, 1170– 1177 (1984). 6715404 PMC2113248 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are efforts aimed at predicting immunogenicity using in silico and in vitro tools.

    “Despite these challenges, there are efforts aimed at predicting immunogenicity using in silico and in vitro tools.49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] De Groot, A.S., McMurry, J. & Moise, L. Prediction of immunogenicity: in silico paradigms, ex vivo and in vivo correlates. Curr. Opin. Pharmacol. 8, 620– 626 (2008). 18775515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using simplified allometry, the volume of distribution scales proportionally with body weight and clearance often follows an exponent between 0.8-0.9 along with body weight scaling.

    “Using this method, the volume of distribution scales proportionally with body weight and clearance often follows an exponent between 0.8–0.9 along with body weight scaling.66”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Deng, R., Iyer, S., Theil, F.P., Mortensen, D.L., Fielder, P.J. & Prabhu, S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs. 3, 61– 66 (2011). 20962582 PMC3038012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sequence alone is not a reliable predictor of immunogenicity; determinants of immunogenicity include product characteristics such as oxidation and deamidation sites, as well as target biology, patient population, dosing routes, and regimen.

    “However, sequence alone is not a reliable predictor of immunogenicity. Determinants of immunogenicity include product characteristics such as oxidation and deamidation sites, as well as target biology, patient population, dosing routes, and regimen.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Singh, S.K. Impact of product‐related factors on immunogenicity of biotherapeutics. J. Pharm. Sci. 100, 354– 387 (2011). 20740683 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ADA response may result in the formation of immune complexes with the mAbs; immune complexes are more likely cleared via FcγR-mediated endocytosis at a different rate than mAb alone and accelerate (or less frequently delay) the overall mAb clearance.

    “ADA response may result in the formation of immune complexes with the mAbs. Varying in size and structure, immune complexes are more likely cleared via FcγR‐mediated endocytosis at a different rate than mAb alone (faster or sometimes slower) and accelerate (or less frequently delay) the overall mAb clearance.45”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Bendtzen, K. Immunogenicity of Anti‐TNF‐alpha Biotherapies: II. Clinical Relevance of Methods Used for Anti‐Drug Antibody Detection. Front Immunol. 6, 109 (2015). 25904911 PMC4389574 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunogenicity in preclinical species cannot predict the incidence of human ADAs but may have utility in characterizing the consequences of potential ADAs.

    “Immunogenicity in preclinical species cannot predict the incidence of human ADAs but may have utility in characterizing the consequences of potential ADAs.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] FDA. Guidance for Industry ‐ Immunogenicity Assessment for Therapeutic Protein Products 2014 [Available from: https://www.fda.gov/downloads/drugs/guidances/ucm338856.pdf.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Therapeutic mAbs with high terminal mannose glycans exhibit fast elimination from systemic circulation and lower efficacy.

    “For example, therapeutic mAbs with high terminal mannose glycans exhibit fast elimination from systemic circulation and lower efficacy.43, 44”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Goetze, A.M. et al High‐mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology. 21, 949– 959 (2011). 21421994 source

      Not checked in the free run.

    • cites [44] Kanda, Y. et al Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N‐linked Fc oligosaccharides: the high‐mannose, hybrid, and complex types. Glycobiology. 17, 104– 118 (2007). 17012310 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once in clinical development, clinical pharmacology studies can identify covariates and potential sources of intersubject variability, establish exposure-response relationships in patients, and aid in development of a dosing regimen.

    “Once in clinical development, clinical pharmacology studies can identify the covariates and potential sources of intersubject variability; establish exposure–response relationships in patients, and aid in development of a dosing regimen.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Gill, K.L., Machavaram, K.K., Rose, R.H. & Chetty, M. Potential Sources of Inter‐Subject Variability in Monoclonal Antibody Pharmacokinetics. Clin. Pharmacokinet. 55, 789– 805 (2016). 26818483 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The specific choice for FIH dose depends on several factors: species cross-reactivity, relevance of animal models, steepness of dose response, PK/PD relationship, nature of toxicity, and precedence of molecules in similar pathways.

    “The specific choice for FIH dose depends on several factors: species cross‐reactivity, relevance of animal models, steepness of dose response, PK/PD relationship, nature of toxicity such as predictability, reversibility, tolerability, manageability, and the precedence of molecules in similar pathways.70”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Chapman, K., Pullen, N., Graham, M. & Ragan, I. Preclinical safety testing of monoclonal antibodies: the significance of species relevance. Nat. Rev. Drug Discov. 6, 120– 126 (2007). 17268483 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 58% of studies used NHPs only and nearly 80% used both NHPs and rodents to determine FIH dose.

    “Based on literature, approximately 58% of studies used NHPs only and nearly 80% used both NHPs and rodents to determine FiH dose.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Tosi, D. et al Clinical Development Strategies and Outcomes in First‐in‐Human Trials of Monoclonal Antibodies. J. Clin. Oncol. 33, 2158– 2165 (2015). 26014300 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MABEL-based approach is the most conservative approach leading to a lower starting dose.

    “While the MABEL‐based approach is the most conservative approach leading to a lower starting dose”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Suh, H.Y., Peck, C.C., Yu, K.S. & Lee, H. Determination of the starting dose in the first‐in‐human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013. Drug Des Devel Ther. 10, 4005– 4016 (2016). PMC5153257 27994442 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PBPK modeling can capture both drug-related and system-related properties across species and add additional insights in translational projection.

    “By integrating physiological parameters, in vitro and in vivo PK data into anatomically and physiologically meaningful compartments, PBPK modeling can capture both drug‐related and system‐related properties across species and add additional insights in translational projection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Clinical pharmacology along with pharmacometric approaches help identify patient-specific covariates, assess the source of variability, explore dose/exposure response relationships, dissect the role of predictive and prognostic biomarkers, and ultimately, establish the dose and dosing regimen for a given treatment.

    “Clinical pharmacology along with pharmacometric approaches help identify patient‐specific covariates, assess the source of variability, explore dose/exposure response relationships, dissect the role of predictive and prognostic biomarkers, and ultimately, establish the dose and dosing regimen for a given treatment.83”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Vicini, P. & Roskos, L.K. Clinical Pharmacology: a Discipline at the Nexus Between Translational Science and Precision Medicine: Commentary on “Enhancing Value of Clinical Pharmacodynamics in Oncology Drug Development: An Alliance Between Quantitative Pharmacology and Translational Science”. Clin. Pharmacol. Ther. 2016. 27984659

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The majority of novel checkpoint inhibitors in cancer immunotherapy exhibit heterogeneous tumor responses and lack predictive biomarkers.

    “since the majority of these therapeutics exhibit heterogeneous tumor responses and lack predictive biomarkers.81”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Garrido, M.J., Berraondo, P. & Troconiz, I.F. Commentary on Pharmacometrics for Immunotherapy. CPT Pharmacometrics Syst. Pharmacol. 6, 8– 10 (2017). 27997736 PMC5270298 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One of the most active areas of bsAbs application is in the field of cancer immunotherapy.

    “One of the most active areas of bsAbs application is in the field of cancer immunotherapy.85, 86, 87”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [85] Chames, P. & Baty, D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 1, 539– 547 (2009). 20073127 PMC2791310 source

      Not checked in the free run.

    • cites [86] Muller, D. & Kontermann, R.E. Bispecific antibodies for cancer immunotherapy: Current perspectives. BioDrugs. 24, 89– 98 (2010). 20199124 source

      Not checked in the free run.

    • cites [87] Gadkar, K. et al Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain. Eur. J. Pharm. Biopharm. 101, 53– 61 (2016). 26820920 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Currently, there are over 60 different bsAbs formats with variations in modular structure, size, affinity/avidity, PK behavior, and intended clinical application.

    “Currently, there are over 60 different bsAbs formats with variations in modular structure, size, affinity/avidity, PK behavior, and intended clinical application.84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Spiess, C., Zhai, Q. & Carter, P.J. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol. Immunol. 67 (2 Pt A), 95– 106 (2015). 25637431 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M252Y/S254T/T256E (YTE) mutations on motavizumab led to a 10-fold increase in affinity for human FcRn at pH 6.0 with no change in affinity at pH 7.4 and significantly increased its half-life in monkeys and in healthy adult humans.

    “M252Y/S254T/T256E (YTE) mutations on motavizumab led to a 10‐fold increase in affinity for human FcRn at pH 6.0 with no change in affinity at pH 7.4 and significantly increased its half‐life in monkeys and in healthy adult humans.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Robbie, G.J. et al A novel investigational Fc‐modified humanized monoclonal antibody, motavizumab‐YTE, has an extended half‐life in healthy adults. Antimicrob. Agents Chemother. 57, 6147– 6153 (2013). 24080653 PMC3837853 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mAbs exhibit limited distribution to the brain, with mAb concentrations determined to be 0.1-0.2% and 0.02% of the steady-state circulating mAb concentration in rodents and cynomolgus monkey, respectively.

    “mAbs exhibit limited distribution to the brain, and mAb concentrations was determined to be 0.1–0.2 % and 0.02 % of the steady‐state circulating mAb concentration in rodents and cynomolgus monkey, respectively.92, 93”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Poduslo, J.F., Curran, G.L. & Berg, C.T. Macromolecular permeability across the blood‐nerve and blood‐brain barriers. Proc. Natl. Acad. Sci. USA 91, 5705– 5709 (1994). 8202551 PMC44065 source

      Not checked in the free run.

    • cites [93] Yadav, D.B. et al Widespread brain distribution and activity following i.c.v. infusion of anti‐beta‐secretase (BACE1) in nonhuman primates. Br. J. Pharmacol. 2017. PMC5659992 28859225 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell-containing tissues.

    “They also showed that there was a strong correlation between CD3 affinity and distribution to T‐cell‐rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell‐containing tissues91”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Mandikian, D. et al Relative Target Affinities of T‐Cell‐Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model. Mol. Cancer Ther. 17, 776– 785 (2018). 29339550 source

      Not checked in the free run.

26 of 26

  • The authors state this as an assumption.

    Free mAb is the driver for biological activities.

    “Free mAb is often the most desirable analyte since it is assumed to be the driver for biological activities.”

  • The paper relies on this without support.

    The FcγR-mediated elimination pathway is not saturable for mAb therapeutics.

    “The FcγR‐mediated elimination pathway is not saturable for mAbs therapeutics; therefore, FcγR binding alone is not expected to impact mAb PK when nonspecific clearance is dominant.”

  • The paper relies on this without support.

    Target-mediated clearance decreases with saturation of the target.

    “Target‐mediated clearance decreases with the saturation of the target, which in turn is dependent on dose.”

  • The paper relies on this without support.

    mAbs are mainly metabolized and eliminated through proteolytic degradation that results in smaller peptides and amino acids.

    “Instead, mAbs are mainly metabolized and eliminated through proteolytic degradation that results in smaller peptides and amino acids.”

  • The paper relies on this without support.

    Systemically administered mAbs exhibit biphasic PK profiles in circulation, with a relatively fast distribution phase followed by a slower elimination phase.

    “Typically, systemically administered mAbs exhibit biphasic PK profiles in circulation, i.e., a relatively fast distribution phase followed by a slower elimination phase.”

  • The paper relies on this without support.

    The administration routes of choice for mAbs are intravenous, subcutaneous, and occasionally intramuscular.

    “The administration routes of choice for mAbs are intravenous (i.v.), subcutaneous (s.c.), and occasionally intramuscular (i.m.).”

  • The paper relies on this without support.

    FcRn binds to the Fc region of IgG in a pH-dependent manner, strong at acidic pH 6.0–6.5 and weak at neutral pH 7.0–7.5.

    “FcRn binds to the Fc region of the IgG in a pH‐dependent manner, i.e., the binding between IgG and FcRn is strong at acidic pH of 6.0–6.5 and weak at neutral pH of 7.0–7.5.”

  • The authors state this as an assumption.

    Dose-normalized drug concentrations in preclinical species are equivalent to humans.

    “based on the assumption that the dose‐normalized drug concentrations in preclinical species are equivalent to humans”

  • The authors state this as an assumption.

    Exposure–response relationships translate across species.

    “exposure–response relationships translate across species”

  • The authors state this as an assumption.

    mAb PK is predictable in humans at a relevant dose range.

    “mAb PK is predictable in humans at a relevant dose range”

  • The paper relies on this without support.

    A high degree of homology between epitopes often signals the likelihood of crossreactivity for a given mAb.

    “A high degree of homology between epitopes often signals the likelihood of crossreactivity for a given mAb.”

  • The paper relies on this without support.

    It is not unusual to have lead candidates that show limited binding to rodent and NHPs are the only relevant species that support toxicity or PD studies.

    “It is not unusual to have lead candidates that show limited binding to rodent and NHPs are the only relevant species that support toxicity or PD studies.”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Isoelectric point, viscosity, immunogenicity, non-specificity, aggregation, and stability are factors related to clinical PK clearance rate.

    “Isoelectric point (pI), viscosity, immunogenicity, non-specificity, aggregation, and stability are factors related to clinical PK clearance rate [34].”

    From Computational and artificial intelligence-based methods for antibody development (2023) · cites this paper as [34]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Overlapping first-in-human study categories exceed 100%

    Minor

    Studies using NHPs only cannot also use both NHPs and rodents. The stated shares-approximately 58% and nearly 80%-therefore cannot both describe the same set of studies.

  • Reported clearance range excludes a listed mAb

    Minor

    Table 1 says recently marketed mAbs have clearance values of 90-560 mL/day, but Table 3 lists avelumab at 590 mL/day.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Janeway C.Immunobiology 5th Edition Garland Publishing;2001.

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Authors
Ovacik, M., & Lin, K.
Affiliations
  • Genentech (US)
  • NGM Biopharmaceuticals (United States) (US)
Corresponding author
Lin, Kedan
ORCID
Lin, Kedan
Venue
Clinical and Translational Science
Publisher
Wiley
Published
2018-08-07
Volume
11
Issue
6
Pages
540-552
ISSN
  • 1752-8054 (ISSN-L)
  • 1752-8062
DOI
10.1111/cts.12567
PMC
PMC6226118
OpenAlex
W2806708871
Semantic Scholar
45578fb88c0eef04cdfc82cd1d5a3b4947c25e9f
Cited by
299
References
96
Citations by year
2026: 49 · 2025: 43 · 2024: 46 · 2023: 44 · 2022: 49 · 2021: 40 · 2020: 22 · 2019: 5 · 2018: 1
FWCI
11.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical and Translational Science (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
monoclonal antibodies, antibody pharmacokinetics, pharmacodynamics, early drug development, antibody development
MeSH terms
Drug Development, Antibodies, Monoclonal, Biological Availability, Clinical Trials as Topic, Decision Making, Half-Life, Humans, Metabolic Clearance Rate, Models, Biological, Tissue Distribution, History, 21st Century, Molecular Targeted Therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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