Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer

Miriam Colombo, Maria Antonietta Rizzuto, Chiara Pacini, Laura Pandolfi, Arianna Bonizzi, Marta Truffi, Matteo Monieri, Francesco Catrambone, Marco Giustra, Stefania Garbujo, Luisa Fiandra, Fabio Corsi, Davide Prosperi, Serena Mazzucchelli

Research output: Contribution to journalArticle

Abstract

The use of therapeutic monoclonal antibodies (mAbs) has revolutionized cancer treatment. The conjugation of mAbs to nanoparticles has been broadly exploited to improve the targeting efficiency of drug nanocarriers taking advantage of high binding efficacy and target selectivity of antibodies for specific cell receptors. However, the therapeutic implications of nanoconjugation have been poorly considered. In this study, half-chain fragments of the anti-EGFR mAb cetuximab were conjugated to colloidal nanoparticles originating stable nanoconjugates that were investigated as surrogates of therapeutic mAbs in triple negative breast cancer (TNBC). Three TNBC cell lines were selected according to EGFR expression, which regulates activation of MAPK/ERK and PI3K/Akt pathways, and to distinctive molecular profiling including KRAS, PTEN, and BRCA1 mutations normally associated with diverse sensitivity to treatment with cetuximab. The molecular mechanisms of action of nanoconjugated half-chain mAb, including cell targeting, interference with downstream signaling pathways, proliferation, cell cycle, and apoptosis, along with triggering of ADCC response, were investigated in detail in sensitive and resistant TNBC cells. We found that half-chain mAb nanoconjugation was able to enhance the therapeutic efficacy and improve the target selectivity against sensitive, but unexpectedly also resistant, TNBC cells. Viability assays and signaling transduction modulation suggested a role of BRCA1 mutation in TNBC resistance to cetuximab alone, whereas its effect could be circumvented using half-chain cetuximab nanoconjugates, suggesting that nanoconjugation not only improved the antibody activity but also exerted different mechanisms of action. Our results provide robust evidence of the potential of half-chain antibody nanoconjugates in the treatment of TNBC, which could offer a new paradigm for therapeutic antibody administration, potentially allowing improved curative efficiency and reduced minimal effective dosages in both sensitive and resistant tumors.

Original languageEnglish
Pages (from-to)3817-3832
Number of pages16
JournalBioconjugate Chemistry
Volume29
Issue number11
DOIs
Publication statusPublished - Nov 21 2018

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Nanoconjugates
Triple Negative Breast Neoplasms
Antibodies
Monoclonal antibodies
Monoclonal Antibodies
Nanoparticles
Oncology
Cell proliferation
Cell death
Therapeutics
Phosphatidylinositol 3-Kinases
Tumors
Assays
Antibody-Dependent Cell Cytotoxicity
Chemical activation
Cells
Modulation
Mutation
Apoptosis
Therapeutic Uses

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Colombo, M., Rizzuto, M. A., Pacini, C., Pandolfi, L., Bonizzi, A., Truffi, M., ... Mazzucchelli, S. (2018). Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer. Bioconjugate Chemistry, 29(11), 3817-3832. https://doi.org/10.1021/acs.bioconjchem.8b00667

Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer. / Colombo, Miriam; Rizzuto, Maria Antonietta; Pacini, Chiara; Pandolfi, Laura; Bonizzi, Arianna; Truffi, Marta; Monieri, Matteo; Catrambone, Francesco; Giustra, Marco; Garbujo, Stefania; Fiandra, Luisa; Corsi, Fabio; Prosperi, Davide; Mazzucchelli, Serena.

In: Bioconjugate Chemistry, Vol. 29, No. 11, 21.11.2018, p. 3817-3832.

Research output: Contribution to journalArticle

Colombo, M, Rizzuto, MA, Pacini, C, Pandolfi, L, Bonizzi, A, Truffi, M, Monieri, M, Catrambone, F, Giustra, M, Garbujo, S, Fiandra, L, Corsi, F, Prosperi, D & Mazzucchelli, S 2018, 'Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer', Bioconjugate Chemistry, vol. 29, no. 11, pp. 3817-3832. https://doi.org/10.1021/acs.bioconjchem.8b00667
Colombo, Miriam ; Rizzuto, Maria Antonietta ; Pacini, Chiara ; Pandolfi, Laura ; Bonizzi, Arianna ; Truffi, Marta ; Monieri, Matteo ; Catrambone, Francesco ; Giustra, Marco ; Garbujo, Stefania ; Fiandra, Luisa ; Corsi, Fabio ; Prosperi, Davide ; Mazzucchelli, Serena. / Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer. In: Bioconjugate Chemistry. 2018 ; Vol. 29, No. 11. pp. 3817-3832.
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AU - Catrambone, Francesco

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N2 - The use of therapeutic monoclonal antibodies (mAbs) has revolutionized cancer treatment. The conjugation of mAbs to nanoparticles has been broadly exploited to improve the targeting efficiency of drug nanocarriers taking advantage of high binding efficacy and target selectivity of antibodies for specific cell receptors. However, the therapeutic implications of nanoconjugation have been poorly considered. In this study, half-chain fragments of the anti-EGFR mAb cetuximab were conjugated to colloidal nanoparticles originating stable nanoconjugates that were investigated as surrogates of therapeutic mAbs in triple negative breast cancer (TNBC). Three TNBC cell lines were selected according to EGFR expression, which regulates activation of MAPK/ERK and PI3K/Akt pathways, and to distinctive molecular profiling including KRAS, PTEN, and BRCA1 mutations normally associated with diverse sensitivity to treatment with cetuximab. The molecular mechanisms of action of nanoconjugated half-chain mAb, including cell targeting, interference with downstream signaling pathways, proliferation, cell cycle, and apoptosis, along with triggering of ADCC response, were investigated in detail in sensitive and resistant TNBC cells. We found that half-chain mAb nanoconjugation was able to enhance the therapeutic efficacy and improve the target selectivity against sensitive, but unexpectedly also resistant, TNBC cells. Viability assays and signaling transduction modulation suggested a role of BRCA1 mutation in TNBC resistance to cetuximab alone, whereas its effect could be circumvented using half-chain cetuximab nanoconjugates, suggesting that nanoconjugation not only improved the antibody activity but also exerted different mechanisms of action. Our results provide robust evidence of the potential of half-chain antibody nanoconjugates in the treatment of TNBC, which could offer a new paradigm for therapeutic antibody administration, potentially allowing improved curative efficiency and reduced minimal effective dosages in both sensitive and resistant tumors.

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