Cited by 365Monoclonal and Polyclonal Antibodies ResearchHER2/EGFR in Cancer ResearchRadiopharmaceutical Chemistry and Applications

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Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors

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Rudnick, Stephen I., Lou, Jianlong, Shaller, Calvin C., Tang, Yong, Klein-Szanto, Andres J.P., Weiner, Louis M., Marks, James D., Adams, Gregory P.·2011·Cancer Research

DOI 10.1158/0008-5472.can-10-2277PMC PMC3077882

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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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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.
ORCID: Lou, Jianlong
Tang, Yong
Weiner, Louis M.
Marks, James D.
Adams, Gregory P.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-03-14
Volume: 71
Issue: 6
Pages: 2250-2259
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-10-2277
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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Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors

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