Epitope Mapping and Computational Analysis of Anti-HPV16 E6 and E7 Antibodies in Single-Chain Format for Clinical Development as Antitumor Drugs

Amici, Carla; Donà, Maria Gabriella; Chirullo, Barbara; Bonito, Paola Di; Accardi, Luisa

doi:10.3390/cancers12071803

Cited by 6 publications

(9 citation statements)

References 38 publications

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“…Recently, we also compared our scFvs to Clinical-Stage Therapeutic antibodies (CSTs) by computational analysis, and observed that they have properties well-conforming antibodies which have already reached Phase I clinical trial [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

Paolini¹,

Amici

Carosi

et al. 2021

J Exp Clin Cancer Res

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Background The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells. Methods Envisioning clinical application of the best characterized anti-HPV16 E6 and –HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed. Results We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway. Conclusion Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

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Section: Discussionmentioning

confidence: 99%

Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

Paolini¹,

Amici

Carosi

et al. 2021

J Exp Clin Cancer Res

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“…Single-chain variable antibody fragments (scFvs) are another area of interest in antitumor management, especially with respect to HPV. These antibodies can be engineered for expression intracellularly, or to target cells directly [47]. Specifically, scFvs have been identified with the ability to bind to epitopes of oncoproteins expressed by HPV-16 (16E7) and interfere with protein function [47].…”

Section: Future Of Hpv Vaccinationmentioning

confidence: 99%

“…These antibodies can be engineered for expression intracellularly, or to target cells directly [47]. Specifically, scFvs have been identified with the ability to bind to epitopes of oncoproteins expressed by HPV-16 (16E7) and interfere with protein function [47]. Other scFvs have been identified that could work by interfering with E7 binding to the pRb tumor suppressor directly [47].…”

Section: Future Of Hpv Vaccinationmentioning

confidence: 99%

“…Specifically, scFvs have been identified with the ability to bind to epitopes of oncoproteins expressed by HPV-16 (16E7) and interfere with protein function [47]. Other scFvs have been identified that could work by interfering with E7 binding to the pRb tumor suppressor directly [47]. A third scFv, which has already demonstrated anti-tumor activity, works by binding cassein kinase II and does not exhibit anti-E7 properties directly [47].…”

Section: Future Of Hpv Vaccinationmentioning

confidence: 99%

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Human Papilloma Virus Vaccination

Rosalik

Tarney

Han

2021

Viruses

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Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide causing a variety of benign and malignant conditions. A significant portion of the global population is infected with HPV, with the virus attributed to causing up to 5% of cancers worldwide. Bivalent, quadrivalent, and nine-valent vaccinations exist to aid in the prevention of these diseases and have been proven to be effective at preventing both benign and malignant disease. While vaccination is readily accessible in more developed countries, barriers exist to worldwide distribution and acceptance of vaccination. Vaccination and screening of HPV infection when used in combination are proven and predicted to decrease HPV related pathology. Improvements in vaccination formulations, for treatment as well as prevention, are actively being sought from a variety of mechanisms. Despite these advancements, and the data supporting their efficacy, there has been substantial delay in obtaining adequate vaccination coverage. In reviewing these challenges and looking forward to new vaccine development—especially within the current pandemic—it is clear from the challenges of HPV we require methods to more effectively encourage vaccination, ways to dispel vaccination myths as they occur, and implement better processes for vaccine distribution globally.

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“…Specific antibodies in a single-chain format (scFvs) able to target the E6 and E7 oncoproteins of high-risk HPVs represent new therapeutic molecules against HPV-associated neoplastic lesions. Amici et al evaluated the antigen-binding capacity of diverse anti-16E7 scFvs by using E7 mutants as well as by performing computational analyses to define length, total net charge, hydrophobicity, polarity, and charge distribution to better adapt the antibodies for clinical use [ 19 ]. Hence, scFvs may represent valid candidates for HPV-related cancer immunotherapy.…”

mentioning

confidence: 99%