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Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers.

ABSTRACT: The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs, and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long-lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing Phase I clinical trial (EudraCT 2011-001104-34).

SUBMITTER: Marchini C

PROVIDER: S-EPMC3653119 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers.

Marchini Cristina C Kalogris Cristina C Garulli Chiara C Pietrella Lucia L Gabrielli Federico F Curcio Claudia C Quaglino Elena E Cavallo Federica F Amici Augusto A

Frontiers in oncology 20130514

The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs, and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has b ...[more]

PMID: 23675574

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Project description:Overexpression of the human epidermal growth factor receptor 2 (HER2) is found in 20-30% of breast cancer tumors (HER2-positive breast cancers) and is associated with more aggressive onset of disease, higher recurrence rate and increased mortality. Monoclonal antibodies (mAb) like trastuzumab and pertuzumab in combination with chemotherapeutics, and trastuzumab-based antibody drug conjugates (ADCs) are used in the clinic to treat these cancers. An alternative targeted strategy (not yet in clinical use) is the encapsulation of chemotherapeutic drugs in immunoliposomes. Such systems may not only facilitate targeted delivery to the tumor and improve intracellular penetration, but also override some of the resistance developed by tumors in response to cytotoxic loads. As a supplement to classical chemotherapeutics (based on organic compounds and conventional platinum-based derivatives), gold compounds are emerging as potential anticancer agents due to their high cytotoxicity and capacity for immunogenic cell death. Here, we describe the development of immunoliposomes functionalized with trastuzumab and pertuzumab; containing simple gold(i) neutral compounds ([AuCl(PR3)] (PR3 = PPh3 (1), PEt3 (2))) generated by the thin-film method to afford Lipo-1-Lipo-2. Trastuzumab and pertuzumab were engrafted onto these liposomes to generate gold-based immunoliposomes (Immunolipo-Tras-1, Immunolipo-Tras-2, Immunolipo-Per-1, Immunolipo-Per-2). We have characterized all liposomal formulations and demonstrated that the immunoliposomes (190 nm) are stable, have high binding affinity for HER2, and display selective cytotoxicity towards HER2-positive breast cancer cell lines. Trastuzumab-based immunoliposomes of a smaller size (100 nm) - encapsulating [AuCl(PEt3)] (2) - have been generated by an extrusion homogenization method. These optimized immunoliposomes (Opt-Immunolipo-Tras-2) have a trastuzumab engraftment efficiency, encapsulation efficiency for 2, and affinity for HER-2 similar to the immunoliposomes obtained by sonication (Immunolipo-Tras-2). While the amount of Au encapsulated is slightly lower, they display almost identical cytotoxicity and selectivity profiles. Moreover, the fluorescently-labeled phosphane drug [AuCl(PPh2-BODIPY)] (3) was encapsulated in both larger (Immunolipo-Tras-3) and smaller (Opt-Immunolipo-Tras-3) immunoliposomes and used to visualize the intracellular localization of the payload. Fluorescent imaging studies found that Opt-Immunolipo-Tras-3 accumulates in the cells more than 3 and that the unencapsulated payload accumulates primarily in lysosomes, while targeted liposomal 3 localizes in mitochondria and ER, hinting at different possibilities for modes of action.

Project description:The increasing and ongoing issue of antibiotic resistance in bacteria is of huge concern globally, mainly to healthcare facilities. It is now crucial to develop a vaccine for therapeutic and preventive purposes against the bacterial species causing hospital-based infections. Among the many antibiotic- resistant bacterial pathogens, the Enterobacter cloacae complex (ECC) including six species, E. Colcae, E. absuriae, E. kobie, E. hormaechei, E. ludwigii, and E. nimipressuralis, are dangerous to public health and may worsen the situation. Vaccination plays a vital role in the prevention of infections and infectious diseases. This research highlighted the construction and design of a multi-epitope vaccine for the E. cloacae complex by retrieving their complete sequenced proteome. The retrieved proteome was assessed to opt for potential vaccine candidates using immunoinformatic tools. Both B and T-cell epitopes were predicted in order to create both humoral and cellular immunity and further scrutinized for antigenicity, allergenicity, water solubility, and toxicity analysis. The final potential epitopes were subjected to population coverage analysis. Major histocompatibility complex (MHC) class combined, and MHC Class I and II world population coverage was obtained as 99.74%, and 98.55% respectively while a combined 81.81% was covered. A multi-epitope peptide-based vaccine construct consisting of the adjuvant, epitopes, and linkers was subjected to the ProtParam tool to calculate its physiochemical properties. The total amino acids were 236, the molecular weight was 27.64kd, and the vaccine construct was stable with an instability index of 27.01. The Grand Average of Hydropathy (GRAVY) (hydrophilicity) value obtained was -0.659, being more negative and depicting the hydrophilic character. It was non-allergen antigenic with an antigenicity of 0.8913. The vaccine construct was further validated for binding efficacy with immune cell receptors MHC-I, MHC-II, and Toll-like receptor (TLR)-4. The molecular docking results depict that the designed vaccine has good binding potency with immune receptors crucial for antigen presentation and processing. Among the Vaccine-MHC-I, Vaccine-MHC-II, and Vaccine-TLR-4 complexes, the best-docked poses were identified based on their lowest binding energy scores of -886.8, -995.6, and -883.6, respectively. Overall, we observed that the designed vaccine construct can evoke a proper immune response and the construct could help experimental researchers in the formulation of a vaccine against the targeted pathogens.

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Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers.

Publications

Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers.

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