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Factors Impacting the Tumor Localization and Distribution of Antibody-Based Therapeutics in Oncology

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Development of Antibody-Based Therapeutics

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Abstract

Distribution of antibody-based therapeutics from the vascular space to the target tumor compartment is an important consideration in designing antibody-based oncology drugs. Mouse tumor models represent a reasonable approach for exploring antibody biodistribution. In general, a number of factors such as molecular size, antibody dose, and the length of in vivo tumor exposure can influence antibody localization and tumor penetration. With a few exceptions, the current available data indicate that at clinically relevant doses (ranging from 1 to 10 mg/kg) and over a reasonable clinical exposure time (days rather than hours), antibody biodistribution into tumors is unlikely to be the most significant factor hindering the clinical efficacy of antibody-based therapeutics. Other factors such as antigenic heterogeneity leading to variable distribution of antibody drugs into the tumor, or intrinsic resistance to antibody-mediated effects, may play a far greater role in the resistance properties impacting the antibody efficacy profiles.

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References

  • Ackerman ME, Pawlowski D, Wittrup KD (2008) Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids. Mol Cancer Ther 7:2233–2240

    Article  PubMed  CAS  Google Scholar 

  • Baker JHE, Lindquist KE, Huxham LA et al (2008) Direct visualisation of heterogeneous extravascular distribution of trastuzumab in human epidermal growth factor receptor type 2 overexpressing xenografts. Clin Cancer Res 14:2171–2179

    Article  PubMed  CAS  Google Scholar 

  • Berndorff D, Borkowski S, Sieger S et al (2005) Radioimunotherapy of solid tumors by targeting extra domain B fibronectin: identification of the best suited radioimmunoconjugate. Clin Cancer Res 11(19 suppl):7053s–7063

    Article  PubMed  CAS  Google Scholar 

  • Blumenthal RD, Fand I, Sharkey RM et al (1991) The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: an autoradiography study. Cancer Immunol Immunother 33:351–358

    Article  PubMed  CAS  Google Scholar 

  • Calvete JA, Newell DR, Wright AF et al (1994) In vitro and in vivo anti-tumor activity of Zeneca ZD0490, a recombinant ricin A-chain immunotoxin for the treatment of colorectal cancer. Cancer Res 54:4684–4690

    PubMed  CAS  Google Scholar 

  • Carver BS, Pandolfi PP (2006) Mouse modelling in oncologic preclinical and translational research. Clin Cancer Res 12:5305–5311

    Article  PubMed  CAS  Google Scholar 

  • Debinski W, Karlsson B, Lindholm L et al (1992) Monoclonal antibody C242-Pseudomonas Exotoxin A: a specific and potent immunotoxin with anti-tumor activity on a human colon xenograft in nude mice. J Clin Invest 90:405–411

    Article  PubMed  CAS  Google Scholar 

  • Dennis MS, Jin H, Dugger D et al (2007) Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent. Cancer Res 67:254–261

    Article  PubMed  CAS  Google Scholar 

  • Duncan R (2009) Development of HPMA copolymer-anticancer conjugates: clinical experience and lessons learnt. Adv Drug Deliv Rev 61:1131–1148

    Article  PubMed  CAS  Google Scholar 

  • Epstein AL, Chem F-M, Taylor CR (1988) A novel method for the detection of necrotic lesions in human cancers. Cancer Res 48:5842–5848

    PubMed  CAS  Google Scholar 

  • Esteban JM, Colcher D, Sugarbaker P et al (1987) Quantitative and qualitative aspects of radiolocaliastion in colon cancer patients of intravenously administered Mab B72.3. Int J Cancer 39:50–59

    Article  PubMed  CAS  Google Scholar 

  • Fidarova EF, El-Emir E, Boxer GM et al (2008) Microdistribution of targeted, fluorescently labelled anti-carcinoembryonic antigen antibody in metastatic colorectal cancer: implications for radioimmunotherapy. Clin Cancer Res 14:2639–2646

    Article  PubMed  CAS  Google Scholar 

  • Jain RK, Baxter LT (1988) Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res 48:7022–7032

    PubMed  CAS  Google Scholar 

  • Juweid M, Neuman R, Paik C et al (1992) Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. Cancer Res 52:5144–5153

    PubMed  CAS  Google Scholar 

  • Lee CM, Tannock IF (2010) The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors. BMC Cancer 10:255–266

    Article  PubMed  Google Scholar 

  • Liu C, Tadayoni BM, Bourret LA et al (1996) Eradication of large colon tumor xenografts by targeted delivery of maytansinoids. Proc Natl Acad Sci USA 93:8618–8623

    Article  PubMed  CAS  Google Scholar 

  • Mayer A, Francis RJ, Sharma SK et al (2006) A phase 1 study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anti-carcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug. Clin Cancer Res 12:6509–6516

    Article  PubMed  CAS  Google Scholar 

  • Mullamitha SA, Ton NC, Oarker GJM et al (2007) Phase 1 evaluation of a fully human anti-av integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res 13:2128–2135

    Article  PubMed  CAS  Google Scholar 

  • Rudnick SI, Adams GP (2009) Affinity and avidity in antibody-based tumor targeting. Cancer Biother Rad 24:155–161

    Article  CAS  Google Scholar 

  • Saleh MN, Sugarman S, Murray J et al (2000) Phase 1 trial of the anti-lewisY drug immunoconjugate BR96-doxorubicin in patients with Lewis Y-expressing epithelial tumors. J Clin Oncol 18:2282–2292

    PubMed  CAS  Google Scholar 

  • Scott AM, Lee F-T, Jones R et al (2005) A phase 1 trial of humanised monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake. Clin Cancer Res 11:4810–4817

    Article  PubMed  CAS  Google Scholar 

  • Schmidt MM, Wittrup KD (2009) A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol Cancer Therapeutics 8:2861–2871

    Article  CAS  Google Scholar 

  • Sugahara KN, Teesalu T, Karmali PP et al (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16:510–520

    Article  PubMed  CAS  Google Scholar 

  • Sugahara KN, Teesalu T, Karmali PP et al (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328:1031–1035

    Article  PubMed  CAS  Google Scholar 

  • Thurber GM, Schmidt MM, Wittrup KD (2008) Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev 60:1421–1434

    Article  PubMed  CAS  Google Scholar 

  • Welt S, Divgi CR, Real FX et al (1990) Quantitative analysis of antibody localization in human metastatic colon cancer: a phase 1 study of monoclonal antibody A33. J Clin Oncol 8:1894–1906

    PubMed  CAS  Google Scholar 

  • Yokota T, Milenic DE, Whitlow M, Schlom J (1992) Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res 52:3402–3408

    PubMed  CAS  Google Scholar 

  • Zahnd C, Kawe M, Stumpp MT et al (2010) Efficient tumor targeting with high affinity designed ankyrin repeat proteins: effects of affinity and molecular size. Cancer Res 70:1595–1605

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Oncology Discovery, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom

    David C. Blakey

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  1. David C. Blakey
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Correspondence to David C. Blakey .

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Editors and Affiliations

  1. Merck Research Laboratory, Merck & CO Inc., California Avenue 901, Palo Alto, 94304, California, USA

    Mohammad A. Tabrizi

  2. Pfizer CTI- New York, East 29th Street 450, New York, 10016, New York, USA

    Gadi G. Bornstein

  3. Takeda California, Inc., E. Grand Avenue 285, South San Francisco, 94080, California, USA

    Scott L. Klakamp

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© 2012 Springer Science+Business Media New York

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Blakey, D.C. (2012). Factors Impacting the Tumor Localization and Distribution of Antibody-Based Therapeutics in Oncology. In: Tabrizi, M., Bornstein, G., Klakamp, S. (eds) Development of Antibody-Based Therapeutics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5955-3_9

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  • DOI: https://doi.org/10.1007/978-1-4419-5955-3_9

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  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-5953-9

  • Online ISBN: 978-1-4419-5955-3

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