Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies

Suárez, Narjara González; Báez, Gretchen Bergado; Rodríguez, Mabel; Pérez, Amelia Gutiérrez; García, Lisset Chao; Fernández, Diana; Pous, Judith Raymond; Ramírez, Belinda Sánchez

doi:10.18632/oncotarget.19958

Cited by 9 publications

(3 citation statements)

References 47 publications

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“…Poly Abs can simultaneously target multiple epitopes of the same or different TAAs. Study indicated that simultaneous inactivation of HER1 and HER2 by specific Poly Abs was able to reduce the viability of a panel of human tumor lines with differential expression levels of HER1 and HER2, and circumvent the resistance mechanism 25 . There is growing recognition that the treatment effect of tumor immunotherapy is affected by many factors besides the antigenicity and/or mutational burden of cancer.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth

Huang

et al. 2018

Int. J. Biol. Sci.

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Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. CAFs regulated the growth and development, invasion and metastasis of primary tumors, as well as response to treatment. Recent studies indicated that monoclonal antibody therapies had limited success, thus more effective polyclonal antibodies (Poly Abs) is urgently needed. Poly Abs is a possible alternative because they target multiple antigens simultaneously. In this report, we prepared Poly Abs by immunizing rabbits with the bFGF-activated fibroblasts. The Poly Abs inhibited the cancer cells proliferation as revealed by MTT analysis. The Poly Abs induced apoptosis as indicated by flow cytometric analysis, and microscopic observation of apoptotic changes in morphology. Compared with the control IgG, Poly Abs significantly inhibited tumor cells migration as indicated by wound healing and transwell analysis in vitro, and lung metastasis analysis in vivo. Serial intravenous injections of Poly Abs inhibited tumor growth in mice bearing murine CT26 colon carcinoma. Ki67 analysis indicated that Poly Abs significantly inhibited tumor cells proliferation, as compared to control Ig G treatments. Our findings suggested that Poly Abs was an effective agent for apoptosis induction, migration and metastasis inhibition. The Poly Abs may be useful as a safe anticancer agent for cancer immunotherapy in the future.

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Section: Discussionmentioning

confidence: 99%

Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth

Huang

et al. 2018

Int. J. Biol. Sci.

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“…Polyclonal antibodies can target several epitopes of the same or different tumor-associated antigens. According to the findings, targeting human epidermal growth factor receptor (HER) 1 and HER2 by particular polyclonal antibodies reduced the viability of a panel of human tumor lines with different HER1 and HER2 expression levels, overcoming the tumor resistance mechanism( 21 ). However, non-specific interaction with the non-tumor antigens or non-target antigens can limit polyclonal antibody applications.…”

Section: Discussionmentioning

confidence: 99%

Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody

Khanahmad

Rahimmanesh²,

Esmaili³

et al. 2023

Research in Pharmaceutical Sciences

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Background and purpose: Despite the widespread utilization of cancer vaccines with specified antigens, the use of whole tumor cell lysates in tumor immunotherapy would be a very promising approach that can overcome several significant obstacles in vaccine production. Whole tumor cells provide a broad source of tumor-associated antigens and can activate cytotoxic T lymphocytes and CD4+ T helper cells concurrently. On the other hand, as an effective immunotherapy strategy, recent investigations have shown that the multi-targeting of tumor cells with polyclonal antibodies, which are also more effective than monoclonal antibodies at mediating effector functions for target elimination, might minimize the escape variants. Experimental approach: We prepared polyclonal antibodies by immunizing rabbits with the highly invasive 4T1 breast cancer cell line. Findings/Results: In vitro investigation indicated that the immunized rabbit serum inhibited cell proliferation and induced apoptosis in target tumor cells. Moreover, in vivo analysis showed enhanced anti-tumor efficacy of whole tumor cell lysate in combination with tumor cell-immunized serum. This combination therapy proved beneficial in significant inhibition of the tumor growth and the established tumor was entirely eradicated in treated mice. Conclusion and implications: Serial intravenous injections of tumor cell immunized rabbit serum significantly inhibited tumor cell proliferation and induced apoptosis in vitro and in vivo in combination with whole tumor lysate. This platform could be a promising method for developing clinical-grade vaccines and open up the possibility of addressing the effectiveness and safety of cancer vaccines.

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“…The effects were associated to direct inhibition of EGF-R activation rather than to receptor internalization and degradation, as the total receptor levels (assessed with a control anti-EGF-R that does not depend on target phosphorylation status for recognition) did not vary upon antibody treatments. Future studies of receptor internalization induced by the antibodies could be performed using a suitable experimental setting, with longer treatment of the cells (8 h or more) as previously described 26 .…”

Section: Affinity Increases Translated Into Enhanced Inhibitory Capacmentioning

confidence: 99%

Affinity-matured variants derived from nimotuzumab keep the original fine specificity and exhibit superior biological activity

Tundidor

Ponce

Chao

et al. 2020

Sci Rep

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Nimotuzumab is a humanized monoclonal antibody against the Epidermal Growth Factor Receptor with a long history of therapeutic use, recognizing an epitope different from the ones targeted by other antibodies against the same antigen. It is also distinguished by much less toxicity resulting in a better safety profile, which has been attributed to its lower affinity compared to these other antibodies. Nevertheless, the ideal affinity window for optimizing the balance between anti-tumor activity and toxic effects has not been determined. In the current work, the paratope of the phagedisplayed nimotuzumab Fab fragment was evolved in vitro to obtain affinity-matured variants. Softrandomization of heavy chain variable region CDRs and phage selection resulted in mutated variants with improved binding ability. Two recombinant antibodies were constructed using these variable regions, which kept the original fine epitope specificity and showed moderate affinity increases against the target (3-4-fold). Such differences were translated into a greatly enhanced inhibitory capacity upon ligand-induced receptor phosphorylation on tumor cells. The new antibodies, named K4 and K5, are valuable tools to explore the role of affinity in nimotuzumab biological properties, and could be used for applications requiring a fine-tuning of the balance between binding to tumor cells and healthy tissues.The epidermal growth factor receptor (EGF-R) remains one of the best-established targets for anti-tumor therapies. This receptor is involved in cellular processes that contribute to the survival of epithelial cells. Deregulation of the EGF/EGF-R pathway by receptor overexpression or constitutive activation promotes tumor cell proliferation, invasion, and is associated with poor prognosis in cancer 1 . Up to now three anti-EGF-R monoclonal antibodies (mAbs) have been approved for clinical use by the FDA: cetuximab (2004), panitumumab (2006) and necitumumab (2015) 2 . Nimotuzumab recognizes the same target and has a long history of therapeutic use 3 , starting with clinical trials since 1998, and first registered by the Cuban regulatory authorities in 2002 4 . Nimotuzumab is currently approved in Cuba for the treatment of childhood and adult glioma, advanced esophageal cancer, and squamous cell carcinoma of the head and neck, in combination with chemo-radiotherapy or radiotherapy alone, and is also registered in 28 additional countries.The availability of several mAbs targeting the same tumor antigen can result in different clinical outcomes in terms of therapeutic efficacy, safety, anti-tumor mechanisms, immunogenicity, patients' sub-population that can receive a benefit, and development of resistance to therapy. The major molecular determinants behind such complex landscape of clinical effects are the origin of constant domains (species and isotype), the strength of binding to the target (affinity) and the topology of interaction with the specific antigen region that is recognized (epitope specificity). Properties associated to the nature of co...

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Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies

Cited by 9 publications

References 47 publications

Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth

Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth

Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody

Affinity-matured variants derived from nimotuzumab keep the original fine specificity and exhibit superior biological activity

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