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Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors
Open accessPublished version of a preprint
Abstract
Antibody drugs are widely used in cancer therapy, but conditions to maximize tumor penetration and efficacy have yet to be fully elucidated. In this study, we investigated the impact of antibody binding affinity on tumor targeting and penetration with affinity variants that recognize the same epitope. Specifically, we compared four derivatives of the C6.5 monoclonal antibody (mAb), which recognizes the same HER2 epitope (monovalent KD values ranging from 270 to 0.56 nmol/L). Moderate affinity was associated with the highest tumor accumulation at 24 and 120 hours after intravenous injection, whereas high affinity was found to produce the lowest tumor accumulation. Highest affinity mAbs were confined to the perivascular space of tumors with an average penetration of 20.4 ± 7.5 μm from tumor blood vessels. Conversely, lowest affinity mAbs exhibited a broader distribution pattern with an average penetration of 84.8 ± 12.8 μm. In vitro internalization assays revealed that antibody internalization and catabolism generally increased with affinity, plateauing once the rate of HER2 internalization exceeded the rate of antibody dissociation. Effects of internalization and catabolism on tumor targeting were further examined using antibodies of moderate (C6.5) or high-affinity (trastuzumab), labeled with residualizing (111In-labeled) or nonresidualizing (125I-labeled) radioisotopes. Significant amounts of antibody of both affinities were degraded by tumors in vivo. Furthermore, moderate- to high-affinity mAbs targeting the same HER2 epitope with monovalent affinity above 23 nmol/L had equal tumor accumulation of residualizing radiolabel over 120 hours. Results indicated equal tumor exposure, suggesting that mAb penetration and retention in tumors reflected affinity-based differences in tumor catabolism. Together, these results suggest that high-density, rapidly internalizing antigens subject high-affinity antibodies to greater internalization and degradation, thereby limiting their penetration of tumors. In contrast, lower-affinity antibodies penetrate tumors more effectively when rates of antibody–antigen dissociation are higher than those of antigen internalization. Together, our findings offer insights into how to optimize the ability of therapeutic antibodies to penetrate tumors. Cancer Res; 71(6); 2250–9. ©2011 AACR.
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“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”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [27]
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Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance
Thurber, G. M., Schmidt, M. M., & Wittrup, K. D. (2008) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2008.04.012 · Cited by 642
Adams, G. P., Schier, R., McCall, A. M., Simmons, H. H., Horak, E. M., Alpaugh, R. K., Marks, J. D., & Weiner, L. M. (2001) · PubMed · Cited by 623
Self-citationPhysiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors.
Jain, R. K. (1990) · PubMed · Cited by 574
Austin, C. D., Mazière, A. M. G. L. D., Pisacane, P. I., van Dijk, S., Eigenbrot, C. W., Sliwkowski, M. X., Klumperman, J., & Scheller, R. H. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-07-0591 · Cited by 507
Schier, R., McCall, A. M., Adams, G. P., Marshall, K. W., Merritt, H., Yim, M., Crawford, R. S., Weiner, L. M., Marks, C. B., & Marks, J. D. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0598 · Cited by 382
Self-citationA modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier.
Fujimori, K., Covell, D. G., Fletcher, J. E., & Weinstein, J. N. (1990) · PubMed · Cited by 356
Schier, R., Bye, J. M., Apell, G., McCall, A. M., Adams, G. P., Malmqvist, M., Weiner, L. M., & Marks, J. D. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0004 · Cited by 291
Self-citationFujimori, K., Covell, D. G., Fletcher, J. E., & Weinstein, J. N. (1989) · PubMed · Cited by 258
Zahnd, C., Kawe, M., Stumpp, M. T., de Pasquale, C., Tamaskovic, R., Nagy‐Davidescu, G., Dreier, B., Schibli, R., Binz, H. K., Waibel, R., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2724 · Cited by 245
Affinity and Avidity in Antibody-Based Tumor Targeting
Rudnick, S. I., & Adams, G. P. (2009) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2009.0627 · Cited by 237
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Research works printed but not linked: 1
- Adams, 1992, Comparison of the pharmacokinetics in mice and the biological-activity of murine L6 and human-mouse chimeric Ch-L6 antibody, Antib Immunoconjug Radiopharm, 5, 81
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Metadata
- Authors
- Rudnick, S. I., Lou, J., Shaller, C. C., Tang, Y., Klein-Szanto, A. J. P., Weiner, L. M., Marks, J. D., & Adams, G. P.
- Affiliations
- Fox Chase Cancer Center (US)
- Authors' Affiliations: 1Developmental Therapeutics Program and 2Pathology Department, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 3Department of Anesthesia, University of California, San Francisco, California; and 4Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Colombia
- Corresponding author
- Adams, Gregory P.
- Venue
- Cancer Research
- Published
- 2011-03-14
- Volume
- 71
- Issue
- 6
- Pages
- 2250-2259
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3077882
- OpenAlex
- W2103364597
- Cited by
- 365
- References
- 33
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 17 · 2023: 21 · 2022: 19 · 2021: 36 · 2020: 30 · 2019: 14 · 2018: 35 · 2017: 19 · 2016: 24 · 2015: 26 · 2014: 24 · 2013: 24 · 2012: 17
- FWCI
- 17.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fox Chase Cancer Center
- National Cancer Institute (R01-CA50633, R01CA118159, T32CA009035, R01CA050633)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- anti-HER2 antibody, antibody affinity, tumor penetration, tumor targeting, antigen uptake, antibody internalization, antibody catabolism, tumor accumulation, trastuzumab, HER2, perivascular spaces, solid tumors
- MeSH terms
- Animals, Antibodies, Monoclonal, Antibody Affinity, Epitopes, Antigens, Neoplasm, Binding, Competitive, Endocytosis, Female, Humans, Immunoglobulin G, Immunohistochemistry, Indium Radioisotopes, Iodine Radioisotopes, Mutation, Neoplasm Transplantation, Ovarian Neoplasms, Time Factors, Tissue Distribution, Transplantation, Heterologous, Mice, SCID, Erb-b2 Receptor Tyrosine Kinases, Cell Line, Tumor, Mice
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