Monoclonal antibodies as immunomodulatory therapy against cancer and autoimmune diseases

Hafeez, Umbreen; Gan, Hui; Scott, Andrew M.

doi:10.1016/j.coph.2018.05.010

Cited by 130 publications

(84 citation statements)

References 62 publications

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“…Monoclonal antibodies are excellent agents for use in both diagnosis and therapy of human cancer. The exquisite specificity of the antibodies for the target antigen also makes them ideal tools for investigating the biological, diagnostic, prognostic and predictive value of their target antigens and for use in targeted therapy of human cancers 10,11,23,24 . We have previously reported the generation of two novel anti-CD109 mAbs by means of hybridoma technology using BxPC-3 human pancreatic cancer cells, a cell line derived from a primary tumour, as the source of immunogen 9 .…”

Section: Discussionmentioning

confidence: 99%

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer

Arias-Pinilla

Dalgleish

Mudan

et al. 2020

Sci Rep

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Monoclonal antibody (mAb) technology is an excellent tool for the discovery of overexpressed cell surface tumour antigens and the development of targeting agents. Here, we report the development of two novel mAbs against CFPAC-1 human pancreatic cancer cells. Using ELISA, flow cytometry, immunoprecipitation, mass spectrometry, Western blot and immunohistochemistry, we found that the target antigens recognised by the two novel mAbs KU44.22B and KU44.13A, are integrin α3 and CD26 respectively, with high levels of expression in human pancreatic and other cancer cell lines and human pancreatic cancer tissue microarrays. Treatment with naked anti-CD26 mAb KU44.13A did not have any effect on the growth and migration of cancer cells nor did it induce receptor downregulation. In contrast, treatment with anti-integrin α3 mAb KU44.22B inhibited growth in vitro of Capan-2 cells, increased migration of BxPC-3 and CFPAC-1 cells and induced antibody internalisation. Both novel mAbs are capable of detecting their target antigens by immunohistochemistry but not by Western blot. These antibodies are excellent tools for studying the role of integrin α3 and CD26 in the complex biology of pancreatic cancer, their prognostic and predictive values and the therapeutic potential of their humanised and/or conjugated versions in patients whose tumours overexpress integrin α3 or CD26. Pancreatic cancer remains one of the deadliest cancer types. In 2018, there were an estimated 458,918 new cases of pancreatic cancer, and 432,242 deaths as a result of pancreatic cancer in 185 countries worldwide 1,2. Pancreatic cancer is predicted to become the second leading cause of cancer death after lung cancer, within the next decade in Western countries 3. At present, the only curative treatment for patients with pancreatic cancer is surgery. However, only a minority of patients are eligible for resection and disease recurrence is a frequent event in many such patients. Historically, gemcitabine-based therapy has been the mainstay for treatment of pancreatic cancer 4. More recently the combination of gemcitabine plus capecitabine has been regarded as the new standard of care in the adjuvant setting 5. Patients with metastatic disease are treated with either FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line in patients with good performance status 6,7. In order to reduce the dismal pancreatic cancer mortality rates, it is essential to discover novel biomarkers for use in the early detection of pancreatic cancer, to discover novel therapeutic targets and to develop novel and more effective therapeutic agents 8,9. Monoclonal antibodies (mAbs) are excellent tools for the discovery of novel overexpressed cell surface antigens and their specific targeting for diagnostic and therapeutic purposes 10,11. To date, 36 mAbs have been approved for cancer treatment in the U.S. and/or European Union, although none for pancreatic cancer yet 12,13. As tumour heterogeneity has been reported both between (i.e. inter-tumour heterogeneity)

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Section: Discussionmentioning

confidence: 99%

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer

Arias-Pinilla

Dalgleish

Mudan

et al. 2020

Sci Rep

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“…With the development of hybridoma technology, mass spectrometry engineering, phage display and transgenic animal technology, the preparation of antibodies has successively transitioned from polyclonal to monoclonal antibodies (20,21). a priority has been the humanization of murine antibodies by genetic engineering, in order to obtain a fully humanized monoclonal antibody with high affinity, stability and biological activity (22,23).…”

Section: Discussionmentioning

confidence: 99%

Affinity improvement of the fully human anti‑TSLP recombinant antibody

Chen

Xian

et al. 2019

Mol Med Report

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Thymic stromal lymphopoietin (TSlP) is a potentially important target for the treatment of asthma and malignancies. However, a fully human antibody reactive with TSlP is currently unavailable for clinical use. in a previous study, a human anti-TSlP-single-chain antibody variable fragment (anti-TSlP-scFv) 84 was selected by phage display from a constructed human scFv library. in the present study, a computer simulation method was developed using Discovery Studio 4.5 software, to increase the affinity of anti-TSLP-scFv-84. Specific primers were designed and mutated dna sequences of anti-TSlP-scFvs were obtained by overlap extension Pcr. The mutant scFvs were expressed in plZ16 and affinity-enhanced anti-TSlP-scFv-M4 was screened using eliSa. However, in general the scFvs have low stability and short half-lives in vivo. Therefore, scFv-84 and scFv-M4 were inserted into eukaryotic expression vectors (pcdna3.1-sp-Fc and PMH3 en -sp-Fc) and then transfected into 293F cells to express anti-TSlP-scFv-Fc. eliSa and western blotting results indicated the size of the anti-TSlP-scFv-Fc to be ~50 kda. Binding of anti-TSlP-scFv-Fc-M4 to TSlP was enhanced compared with the pre-mutated scFv-Fc-84. The affinity of the mutated recombinant antibody was determined using the Biacore technique and found to be ~10-fold greater than the pre-mutated antibody.

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“…). Some therapeutic monoclonal antibodies (mAbs) are designed to bind a tumor antigen and induce cell death through various mechanisms or to carry tumoricidal substances . In addition, a newer class of mAbs known as bispecific T‐cell enhancing antibodies has been designed to simultaneously target a tumor‐associated antigen and a T‐cell antigen (e.g., CD19 and CD3, respectively), which results in enhanced co‐localization of T cells and tumors .…”

Section: Breaking Immunological Tolerance To Cancer With Car T Cellsmentioning

confidence: 99%

An introduction to chimeric antigen receptor (CAR) T‐cell immunotherapy for human cancer

et al. 2019

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Chimeric antigen receptor (CAR) T‐cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patient's body to attack and destroy chemotherapy‐resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T‐cell therapy of B‐cell malignancies. This resulted in two recent FDA approvals of CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia and diffuse large B‐cell lymphoma. Thus, CAR T cells are arguably one of the first successful examples of synthetic biology and personalized cellular cancer therapy to become commercially available. In this review, we introduce the concept of using CAR T cells to break immunological tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in the context of predicting clinical responses, and offer prospects for developing next‐generation CAR T cell‐based approaches that will improve outcome.

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Monoclonal antibodies as immunomodulatory therapy against cancer and autoimmune diseases

Cited by 130 publications

References 62 publications

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer

Affinity improvement of the fully human anti‑TSLP recombinant antibody

An introduction to chimeric antigen receptor (CAR) T‐cell immunotherapy for human cancer

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