The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

  • LOG IN
  • BECOME A MEMBER
  • About
    • Mission & Activities
    • Directors and Officers
    • Marketing & Promotions
    • The Antibody Society’s Committees
      • Meetings Committee
      • AIRR Community Working Groups & Sub-Committees
    • Sponsors & Partners
  • Society meetings
    • Computational Antibody Discovery: State of the Art
      • Computational Antibody Discovery Symposium Participants
    • Harnessing Cytokines for Cancer Immunotherapy Symposium
    • Biopharmaceutical Informatics Symposium
    • Emerging Cancer Therapies Leveraging Gamma-Delta Effector T cells Symposium
    • Emerging Immunotherapeutics for Ovarian Cancer Symposium
    • AIRR Community Meetings
    • Antibody Engineering & Therapeutics (US) 2024
      • 2022 Antibody Engineering & Therapeutics
      • 2020 Antibody Engineering & Therapeutics
      • 2019 Antibody Engineering & Therapeutics
      • 2018 Antibody Engineering & Therapeutics
      • What is INN a Name?
        • INN issue updates
    • Antibody Engineering & Therapeutics Europe 10 – 12 June, 2025 | Congress Center, Basel Switzerland.
      • Scientific Advisors, Antibody Engineering & Therapeutics Europe
    • FOCIS Symposia
  • AIRR Community
    • AIRR Community News
    • AIRR Community Newsletter
    • AIRR Community Seminar Series
    • AIRR Community Meetings
      • Zooming into the Community III
      • AIRR Community Meeting VII – Learnings and Perspectives
      • AIRR Community Special Event 2023  – Zooming in to the Community II
      • AIRR Community Meeting VI: “Exploring New Frontiers”
      • AIRR Community Meeting V: “Zooming in to the AIRR Community”
      • AIRR Community Meeting V Pre-Meetings
        • AIRR-seq in the Pandemic
        • AIRR-seq Biological Standards and Workflows
      • AIRR Community Special Event: “Response to COVID-19”
      • AIRR Community Meeting IV: “Bridging the Gaps”
      • AIRR Community Meeting III
        • Day 1
        • Day 2
        • Day 3
        • Day 4
      • AIRR Community Meeting II
      • AIRR Community Meeting I
    • On AIRR – An AIRR Community Podcast
    • AIRR Data Commons
    • AIRR-C Germline Database Resources
    • AIRR Community Publications
    • AIRR Community Working Groups
      • Biological Resources Working Group
      • Common Repository Working Group
      • Diagnostics Working Group
      • Germline Database Working Group
      • Legal and Ethics Working Group
      • Software Working Group
      • Standards Working Group
    • AIRR Community Sub-Committees
      • Communications Sub-Committee
      • Executive Sub-Committee
      • Inferred Allele Review Committee
      • Meetings Sub-Committee
      • Strategic Planning Sub-Committee
    • AIRR Community Webinar Series
    • AIRR Community Calendar
    • AIRR Community Resources
  • Members only
    • Login
    • Note to members
    • Member discount codes
    • 2025 Calendar of Events
    • James S. Huston Antibody Science Talent Award
      • 2024 James S. Huston Antibody Science Talent Award Recipient
      • 2023 James S. Huston Antibody Science Talent Award Recipient
      • 2022 James S. Huston Antibody Science Talent Award Recipient
      • 2021 James S. Huston Antibody Science Talent Award Recipient
      • 2020 James S. Huston Antibody Science Talent Award Recipient
      • Huston Award submission guidelines
    • Research Competitions
      • Research Competition Winners
    • Science Writing Competition
      • Science Writing Competition Winners
    • Imaging Competition
      • Imaging Calendar Competition winners
        • The Antibody Society 2025 Calendar
        • The Antibody Society 2024 Calendar
    • Antibodies in early-stage studies
    • Presentations
  • Upcoming meetings in 2025
  • Web Resources
    • Society Publications
    • Antibody News
    • Antibody News Podcast
    • Antibody therapeutics approved or in regulatory review in the EU or US
      • Antibody therapeutics product data
    • Antibodies in late-stage clinical studies
    • Research Resources
    • Education Resources
  • Career Center
    • Career Shorts
  • Learning Center
    • Upcoming Webinars in 2025
    • The Antibody Series Lectures
    • Antibody Discovery & Development
    • Adaptive Immune Receptor Repertoires
    • Antibodies to Watch
    • Commercializing Antibody Therapeutics
    • Antibody Validation
      • 4th International Antibody Validation Meeting, Sep 2023
    • Snakebite antivenoms: Global challenges and progress toward recombinant antibody therapeutics
You are here: Home / Archives for EGFR

Searching for alternatives in anti-EGFR-based therapies: New uses for antibody 528

April 15, 2021 by The Antibody Society

Post by Raquel Barroso Ferro, University of Aberdeen

Epidermal growth factor receptor (EGFR) is a well known and validated target for monoclonal antibody (mAb) therapeutics. Three anti-EGFR antibodies are currently marketed, cetuximab, necitumumab, and panitumumab. Cetuximab, a recombinant chimeric (human-mouse) monoclonal antibody (mAb) was the first approved, in February 2004, for treatment of colorectal cancer in patients who failed to respond to irinotecan-based chemotherapy. [1] By binding to EGFR with high affinity, the anti-EGFR antibodies prevent EGF, the ligand to EGFR, binding, and therefore block receptor activation and subsequent pro-survival and proliferation-associated signaling pathways. Therefore, in tumors that depend on this receptor to grow, blocking EFGR can halt tumor progression. This is critical, as patients whose tumors had elevated levels of EGFR/EGF were more likely to have aggressive disease, and therefore a poorer prognosis. [2]

Patients commonly become resistant to anti-EGFR antibody therapies through mutational escape. Cetuximab, necitumumab, and panitumumab bind relatively close epitopes and even share epitope regions on EGFR domain III. [3-5] Whilst a mutation in EGFR can make tumors resistant to one antibody but still susceptible to the remaining two such as in the case of S492R that blocks cetuximab binding but panitumumab remains able [5], there are many mutations that can block a tumor’s susceptibility to all three antibodies simultaneously. [6]

Another anti-EGFR mAb, derived from mouse and known as 528, was first reported in the early 1980s. [7,8] Makabe and colleagues [9] recently reported that, while 528 also binds EGFR domain III, its epitope includes a loop formed by residues 353–362 that is not part of the binding sites of cetuximab, necitumumab, and panitumumab. Thus, tumors that are resistant to all three of the currently available antibodies could in theory be susceptible to 528. Although additional studies are required to accurately deduce the interaction of EGFR and 528, compare 528 to the existing therapies, and assess the effects of various EGFR mutations, these initial findings by Makabe and colleagues are intriguing and represent a worthwhile avenue to explore.

Scientists have also investigated 528’s anti-EGFR binding capabilities in bispecific formats that may have therapeutic potential. Humanized versions of 528’s variable region and the anti-CD3 variable region derived from OKT-3, an immunosuppressant drug, were used to construct a bispecific molecule, hEx3, with the aim of bridging T cells to EGFR on cancer cells, thereby targeting the cancer cells for destruction. [10] This bispecific construct was shown to form functional tetramers. [11] The cytotoxicity of hEx3 could be enhancement by affinity maturation [12], by rearranging the variable domain order [13, 14] and by generating Fc fusions. [14, 15 Taken together, the findings of these studies are intriguing. The simple rearrangement of the heavy and light domains from heavy-light to light-heavy substantially enhanced the cytotoxic anti-tumor activity of the hEx3 diabody, as did the introduction of a LH-HY52W mutation hypothesised to increasing affinity of the 528 variable region and its target, EGFR. Moreover, the engineered molecules had enhanced anti-tumour killing in vivo. [15] This result may be associated with increased valency or perhaps through the reduction of serum clearance, which is currently an obstacle to use of non-native, truncated antibody formats. [16]

Overall, anti-EGFR based antibody therapeutics utilizing 528’s epitope-binding region may present new avenues of attack due to its distanced binding site compared to existing therapies. Importantly, nuanced changes to antibody structures, including simple domain rearrangements and alteration of the amino acid sequence, could translate into substantial changes to efficacy.

References
1.       Wong, SF. (2005). Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. 47(6): 684-694.
2.       Chen J, et al. Expression and function of the epidermal growth factor receptor in physiology and disease. Physiol Rev. 2016. PMID: 33003261.
3.       Li, S. et al. (2005). Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer. Cell. 7; 301–311.
4.       Bagchi, A. et al. (2018). Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance. Mol. Cancer. Ther. 17; 521–531. DOI: 10.1158/1535-7163.MCT-17-0575.
5.       Sickmier, E. A. et al. (2016). The panitumumab EGFR complex reveals a binding mechanism that overcomes cetuximab induced resistance. PLoS ONE 11, e0163366. DOI: 10.1371/journal.pone.0163366.
6.       Arena, S. et al. (2015). Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin. Cancer Res. 21; 2157–2166. DOI: 10.1158/1078-0432.CCR-14-2821.
7.       Kawamoto et al. (1983). Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. PNAS. 80 (5) 1337-1341.
8.       Gill GN, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J. Biol. Chem. 1984;259:7755–7760. doi: 10.1016/S0021-9258(17)42857-2.
9.       Makabe et al. (2021). Anti-EGFR antibody 528 binds to domain III of EGFR at a site shifted from the cetuximab epitope. Sci. Rep. 11: 5790.
10.   Asano et al. (2006). Humanization of the bispecific epidermal growth factor receptor × CD3 diabody and its efficacy as a potential clinical reagent. Clin Cancer Res. 12(13). DOI: 10.1158/1078-0432.CCR-06-0059.
11.   Asano et al. (2010). Highly enhanced cytotoxicity of a dimeric bispecific diabody, the hEx3 tetrabody. J. Biol. Chem. 285(27); 20844-20849.
12.   Nakanishi, T. et al. (2013) Development of an affinity-matured humanized anti-epidermal growth factor receptor antibody for cancer immunotherapy. Protein Eng. Des. Sel. 26, 113–122.
13.   Asano et al. (2013). Domain order of a bispecific diabody dramatically enhances its antitumor activity beyond structural format conversion: The case of the hEx3 diabody. Prot. Eng. Des. Sel. 26(5): 359-367.
14.   Asano, R. et al. (2014) Rearranging the domain order of a diabody-based IgG-like bispecific antibody enhances its antitumor activity and improves its degradation resistance and pharmacokinetics. MAbs 6, 1243–1254.
15.   Asano et al. (2020). Build-up functionalization of anti-EGFR × anti-CD3 bispecific diabodies by integrating high-affinity mutants and functional molecular formats. Sci. Rep. 10; 4913.
16.   Wu et al. (1996).  Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers. Immunotechnology. 2(1): 21-36. DOI: 10.1016/1380-2933(95)00027-5.

Filed Under: Antibody therapeutic Tagged With: antibody therapeutics, EGFR

mabs

mabs

The Official Journal of The Antibody Society

Career Center

Our Career Center is a premier resource to connect highly qualified talent with matching career opportunities. Visit for details on over 800 jobs!

AIRR Community

AIRR Community

The Adaptive Immune Receptor Repertoire Community is a research-driven group organizing around the use of high-throughput sequencing technologies to study antibody/B-cell and T-cell receptor repertoires.

Recent Posts

  • Zooming into the Community III Starts Tomorrow! May 20, 2025
  • Exciting news – The AIRR Community is turning 10! 🎂 May 8, 2025
  • The Antibody Society (TAbS): Win a FREE Attendance Pass to AET Basel & Present A Poster: Call For Abstracts! March 26, 2025

Archives

Follow us online

  • Email
  • LinkedIn
  • Twitter
  • YouTube
  • Home
  • Privacy & Terms of Use
  • About
  • Directors and Officers
  • Advisors
  • Sponsors & Partners
  • Mission & Activities
  • Join the Society
  • Membership Levels
  • Members only
  • Login
  • Antibody therapeutics approved or in regulatory review in the EU or US
  • Meeting reports
  • Presentations
  • Contact

©2015 - scicomvisuals