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

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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  • 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”

    From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [27]

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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
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
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fox Chase Cancer Center
  • National Cancer Institute (R01-CA50633, R01CA118159, T32CA009035, R01CA050633)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › 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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