Efficacy of aerosol therapy of lung cancer correlates with EGFR paralysis induced by AvidinOX-anchored biotinylated Cetuximab

Santis, Rita De; Rosi, Antonio; Anastasi, Anna Maria; Chiapparino, Caterina; Albertoni, Claudio; Leoni, Barbara; Pelliccia, Angela; Santapaola, Daniela; Carollo, Valeria; Marra, Emanuele; Aurisicchio, Luigi; Arseni, Brunilde; Pacello, Maria Lucrezia; Palmieri, Gabriella; Battella, Simone; Petronzelli, Fiorella; Milazzo, Ferdinando Maria

doi:10.18632/oncotarget.2409

Cited by 12 publications

(26 citation statements)

References 49 publications

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“…This phenomenon had been previously seen in experiments with biotinylated Cetuximab and Panitumumab and shown to be dependent on a hook effect on the AvidinOX binding [8]. …”

Section: Resultssupporting

confidence: 53%

AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies

et al. 2017

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The oxidized version of Avidin, known as AvidinOX, was previously shown to link to tissue proteins upon injection or nebulization, thus becoming a stable receptor for biotinylated therapeutics. AvidinOX is currently under clinical investigation to target radioactive biotin to inoperable tumor lesions (ClinicalTrials.gov NCT02053324). Presently, we show that the anti-ErbB2 monoclonal antibodies Trastuzumab and Pertuzumab can be chemically biotinylated while maintaining their biochemical and biological properties. By using several and diverse experimental conditions, we show that when AvidinOX is conjugated to tumor cells, low antibody concentrations of biotinylated Trastuzumab (bTrast) or Pertuzumab (bPert) prevent internalization of ErbB2, induce endoplasmic reticulum stress, cell cycle arrest and apoptosis leading to inhibition of proliferation and ErbB2 signaling. Moreover, we found that the treatment is able to induce down-modulation of ErbB2 thus bypassing the known resistance of this receptor to degradation. Interestingly, we show that AvidinOX anchorage is a way to counteract agonistic activities of Trastuzumab and Pertuzumab. Present data are in agreement with previous observations from our group indicating that the engagement of the Epidermal Growth Factor Receptor (EGFR) by AvidinOX-bound biotinylated Cetuximab or Panitumumab, leads to potent tumor inhibition both in vitro and in animal models. All results taken together encourage further investigation of AvidinOX-based treatments with biotinylated antibodies directed to the members of the EGFR family.

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“…This phenomenon had been previously seen in experiments with biotinylated Cetuximab and Panitumumab and shown to be dependent on a hook effect on the AvidinOX binding [8]. …”

Section: Resultssupporting

confidence: 53%

AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies

et al. 2017

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“…In fact, we recently published results that support the potential use of nebulized AvidinOX as an anchoring agent for nebulized biotinylated monoclonal antibodies (including cetuximab) for the topical treatment of lung cancer. Surprisingly, the in vitro potency of bCet, panitumumab, trastuzumab and pertuzumab is improved by the presence of AvidinOX on the surface of tumor cells (19,20), suggesting that AvidinOX could be used as a delivery platform for a variety of potential therapeutic applications. Intra-tumor administration of AvidinOX shares similarities with other procedures common in clinical practice for diagnostic (i.e.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of intra‑tumor AvidinOX and low systemic dose biotinylated cetuximab, with and without cisplatin, in an orthotopic model of head and neck cancer

Vesci

Carollo²,

Rosi

et al. 2019

Oncol Lett

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In a previous study, the efficacy of low intraperitoneal doses of biotinylated cetuximab (bCet) in mice with subcutaneous tumor xenografts of human head and neck cancer (HNC) treated intra-tumors with AvidinOX was reported. Taking into account that the current standard treatment for HNC is the combination of cetuximab and cisplatin, the present study investigated the activity of AvidinOX-targeted bCet with and without cisplatin in an orthotopic model. The results confirmed that administration of intra-tumor AvidinOX makes an otherwise inactive dose of bCet effective in reducing tumor growth, and the addition of a low dose of cisplatin further improved tumor growth inhibition. Supporting the in vivo data, immunohistochemical staining of tumor masses from mice treated with AvidinOX, bCet and cisplatin exhibited the highest tumor cell damage and the lowest angiogenic activity among all treatment groups, measured as the number of γ-H2A.X and cleaved caspase-3-positive cells, and vascular endothelial growth factor-C and platelet and endothelial cell adhesion molecule 1-positive cells, respectively. AvidinOX is currently under clinical investigation to assess its use in delivering radioactive biotin to inoperable tumor lesions (ClinicalTrials. gov: NCT02053324 and NCT03188328). The present study further supported the potential clinical use of AvidinOX to target low bCet doses to inoperable tumor lesions, with or without an additional low dose of cisplatin. Since low doses of highly expensive monoclonal antibodies become effective with AvidinOX and low dose cisplatin, such therapies promise to be cheaper and less toxic than current treatments.

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“…70 This peculiar phenomenon, which is related to the inhibition of the targeted receptor trafficking, could allow significant reduction of antibody doses with consequent reduction of toxicity and costs. Pre-clinical proof of concept of this principle has been previously obtained in models of head and neck 71 and aerosol therapy of lung cancer 72 with the anti-EGFR antibody cetuximab. Our group also recently produced an ADC using trastuzumab to target epigenetic modulation to tumor cells.…”

Section: New Products/new Mechanisms Of Actionmentioning

confidence: 99%

Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy

Santis

2020

mAbs

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Over the past 3 decades, monoclonal antibodies and their related derivatives, including recently approved antibody-drug conjugates, conquered a central role in cancer therapy because of their contribution to improve survival, time to progression and quality of life of patients compared to chemotherapy protocols. This review summarizes information on approved original and biosimilar products, as well as investigational antibody-based therapeutics, targeting ErbB2. This target has been selected as a paradigmatic example because of its relevant role in sustaining the malignancy of major cancer diseases including, breast, gastric and other chemotherapy-resistant solid tumors. This work analyzes the drivers affecting research and development of next-generation anti-ErbB2 immunotherapeutics, taking into account unmet medical needs and pharmacoeconomic issues related to sustainability. The analysis may help with the design of future research and development strategies.

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Efficacy of aerosol therapy of lung cancer correlates with EGFR paralysis induced by AvidinOX-anchored biotinylated Cetuximab

Cited by 12 publications

References 49 publications

AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies

AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies

Therapeutic efficacy of intra‑tumor AvidinOX and low systemic dose biotinylated cetuximab, with and without cisplatin, in an orthotopic model of head and neck cancer

Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy

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