A REVIEW ON TRANSLATIONAL PERSPECTIVE AND EFFICACY OF DIFFERENT ENGINEERED THERAPEUTIC ANTIBODIES

A REVIEW ON TRANSLATIONAL PERSPECTIVE AND EFFICACY OF DIFFERENT ENGINEERED THERAPEUTIC ANTIBODIES

Camellia Roy and Tamalika Chakraborty ^*

Department of Biotechnology, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Panihati, Kolkata - 700114, West Bengal, India.

ABSTRACT: From bench to bedside, clinical research had always played as a convenient tool in the field of cancer biology to inquire about the effectiveness of different anticancer drugs on different human-derived cancer cell lines. According to the American Cancer Society, nearly 4000 new cases and 1600 deaths predicted in 2019 in the United States. Besides, to these alarming statistics, rising cost and health-related complications associated with treatments had made the research of cell lines on the anticancer drug more relevant. This article providing a comprehensive review of cancer, advanced development of the anticancer drugs, and a brief inference on progression-free survival rate (PFS) of the following anticancer and engineered monoclonal antibody drugs are discussed.

Anticancer agent, Cancer cell line, Progression-free survival (PFS), Hybridoma Technology

INTRODUCTION: In the epoch of being healthy cancer has been diagnosed in one out of 10 men and women. Nuclei of normal cells containing DNA made up of nucleotides gets damaged causing mutation. The mutations caused due to exposure of harmful UV radiations; decrease in exercises; increase in specific types of diets that cause quandaries in the cell cycle. According to numerous data collected from different programs; centers and registries exhibited that in spite of early detection and quality of treatment still, cancer remains a terminal health peril amongst people around the globe. Possible studies report about the incidence rate of cancer that is 20% more in men than in women.

Surveys conducted in the United States of America exhibited that breast, prostate; lung & bronchus are the most common types of cancer found in males and females. As cancer is not homogeneous it makes the treatment complicated because there may be three, four, five, or six different slight variations in the cancer cells as known cancer is the constellation of over two hundred diseases having similar characteristics but are different from each other in their mechanism. Common treatments directed to patients are surgery or radiation or chemotherapy. The regular treatment is known as chemotherapy, where various anticancer drugs alone or synergism of drugs are administered by IV.

The objective of this review is to assemble different cancer cell lines from the American Type Culture Collection (ATCC) and MI Bioresearch with their histotype and morphology with effect on different anticancer drugs along with engineered monoclonal antibodies (mAbs) simultaneously including a comparative investigation on progression-free survival (PFS) to decline the rate of cancer in near future.

Role of Cancer Cell Lines: When cells were cultured in-vitro, it propagated into primary culture followed by sub-culture to produce cell lines and distinguished into two kinds of cultures:

(1) Monolayer (anchorage-dependent) culture: cells cultured from an organ or tissue such as epithelial cells and fibroblasts. (2) The suspension (anchorage-independent) culture: cells cultured from hematopoietic cells such as leukemia cells; multiple melanoma cells. Cancer cell lines procured from patients who underwent aggressive cancers. Advancement in cancer pathobiology shows the availability of different innovative models to review various kinds of diseases ¹. Study of cancer relies on the use of primary tumors ²; paraffin-embedded samples²; cancer cell lines ²; xenografts ^{1, 3-4}; tumor primary cell cultures and/or genetically engineered mice ⁵. Cell lines emerge as an expedient alternative to overcome different concerns; easily manipulate and can be molecularly characterized in the development of unique anticancer drugs.

Additionally, it also helps to discern the action mechanism of already used chemotherapeutic drugs. According to various experiments conducted at the laboratories and literature surveys exhibited, to examine the therapeutic efficacy of different FDA approved anticancer drugs on cell lines of Homo sapiens (human), Mus musculus (Mouse), Caviaporcellus (Guinea pig), Sarcophilus harrisii (Tasmanian devil) (Sarcophilus laniarius), Chlorocebus aethiops (Green monkey) were used ⁴.

TABLE 1: DIFFERENT TYPES OF HISTOTYPES AND MORPHOLOGY OF CELL LINES DERIVED FROM HUMANS (HOMO SAPIENS) FOR TREATING DIFFERENT CANCERS ^{4, 6-7}

Antibody engineering, where various antibody domains are combined to generate customized antibodies showing specialized binding properties and desirable effector functions ⁹. This hybridoma technology was developed by Köhler and Milstein and now to improve the therapeutic efficacy to treat cancer, antibodies are engineered to make mutant proteins of higher affinity or small molecular variants or changed functional properties of the original antibody. Lately, this technology has led to the approval by the United States Food and Drug Administration (FDA) of 21 antibodies for cancer immunotherapy ¹⁰. Therefore, different FDA approved anticancer drugs with their mode of action (MoA), pharmacology and cell lines worked on are shown:

Muromonab-cluster of differentiation 3 (CD3) (Orthoclone OKT3®) was the very first approved monoclonal antibody by the United States Food and Drug Administration (FDA) ¹¹.

Using the hybridoma technology IgG2a antibody developed that blocked CD3-mediated activation of T cells and was instrumental in the prevention of organ rejection after transplantation.

Later, it was witnessed that patients with Orthoclone OKT3® developed a significant percentage of anti-drug antibodies known as a “human anti-mouse antibody” (HAMA) response leading to the inactivation and removal of the murine antibody and prevents the use of multiple administrations of the antibody required for cancer therapy.

An antibody made by combining genetic material from a nonhuman source (mouse) with genetic material from a human being to increase efficacy and decreasing immunogenicity is called chimerization and used in treatments.

An antibody made by combining genetic material from a nonhuman source (mouse) with genetic material from a human being to increase efficacy and decreasing immunogenicity is called chimerization and used in treatments.

Approved oncology therapeutic antibodies are human IgG1, IgG2, and IgG4.

Rituximab was the first chimeric therapeutic antibody to treat cancer.

Newly engineered antibodies are:

Cyramza (Ramucirumab): A recombinant human IgG1 monoclonal antibody to treat hepatocellular carcinoma (HCC) ^12-14.

Herceptin Hylecta: (Combination of trastuzumab with hyaluronidase enzyme) is a humanized antibody to treat HER2-overexpressing breast cancer ¹⁶.

Polivy (Polatuzumabvedotin-piiq): Supposed to be a chimeric therapeutic antibody as it is indicated for use in combination with bendamustine plus Rituxan (rituximab) (BR) to treat large B-cell lymphoma ^{18, 48-49}.

Tecentriq (Atezolizumab): Humanized mono-clonal antibody specified to treat extensive-stage small cell lung cancer and triple-negative breast cancer ^{50, 61}.

Gazyva (Obinutuzumab): It is a humanized antibody used to treat previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) ⁵¹.

Panitumumab (Vectibix®): It is the first fully humanized IgG2 approved drug ⁵².

Trastuzumab: It is the humanized IgG1 therapeutic antibodies to treat cancer, such as metastatic breast cancer ⁵³.

Avelumab (Bavencio): It is an FDA approved humanized IgG1 monoclonal antibody directed to PD-L1 that blocks the binding between PD-1 and PD-L1 without affecting PD-1/ PD-L2 interactions to treat Merkel cell carcinoma and urothelial carcinoma. The mode of action demonstrates the potential to utilize both adaptive and innate immune mechanisms to destroy cancer cells ⁴⁵.

Pharmacology: It is treating metastatic Merkel cell carcinoma (MCC) of adults and pediatric patients around 12 years or above, urothelial carcinoma ¹¹.

Mode of Action: Being a PD-L1 blocking antibody where it binds through the FG loops 7 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. In this manner, the interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. The mode of action demonstrates the potential to utilize both adaptive and innate immune mechanisms to destroy cancer cells ^{22, 33}.

Cell Lines Effect: Worked against a panel of triple-negative breast cancer (TNBC) cells.

Panobinostat: A histone deacetylase (HDAC) inhibitor is an FDA approved new agent for multiple myeloma. According to literature surveys, it demonstrates that panobinostat is applied when bortezomib shows no response, still, it's not clear how these drugs work. HDAC inhibitors target epigenetics that is they change the pattern of genes the cell expresses and not the genes themselves. The function of the HDAC inhibitor is it blocks the removal of acetyl groups from histone proteins and reactivates silenced genes. In phase III PANORAMA trial included a total of 768 patients who had relapsed or had refractory MM. Before this trial, all the patients had already received one to three treatments. Trial's result showed that the combination of panobinostat and bortezomib offered the opportunity to extend the duration of PFS and overcome the potential bortezomib resistance ^{11, 27}.

Pharmacology: Evidence shows and indicates that HDAC inhibitors work differently in Multiple Myeloma (MM).

Mode of Action: Deacetylase (DAC) inhibitor is responsible for regulating the acetylation of proteins in the body along with different functions in various vital processes, including replication and repair of DNA; remodeling of chromatin; transcription; progression of the cell cycle; protein degradation and cytoskeletal reorganization. Mode of action of panobinostat is inhibition of class I; class II and class IV proteins also DAC proteins are overexpressed in Multiple Myelomas (MM) ¹¹.

Cell Lines Worked Against: From literature, the study has shown that panobinostat showed cytotoxic activity worked against cell lines such as KMS-12PE, KMS-18, LP-1, NCI H929, KMS-11, RPMI8226, OPM-2, and U266.

Ixazomib (NINLARO): It is the first oral proteasome inhibitor with lenalidomide for the treatment of MM, who has at least received one prior therapy. It is a boronate proteasome inhibitor also an N-capped dipeptidyl leucine boronic acid. The mechanism of action is reversible. It binds and inhibits the beta 5 chymotrypsin-like proteolytic site of the 20S proteasome with a half-maximal IC₅₀ ²⁶.

Pharmacology: It induces apoptosis in multiple myeloma cells, treating Hepatocellular carcinoma (HCC) ²⁵.

Mode of Action: This second-generation proteasome inhibitor (PI) is an N-capped dipeptidyl leucine boronic acid. It reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. When its concentration increases, likewise seem to inhibit the proteolytic β1 and β2 subunits and induce accumulation of ubiquitinated proteins ^{11, 24}.

Cell Lines Worked Against: HepG2, Hep3B, SNU-475, the cytotoxic effect on IMR-32, NGP, NB-19, SH-SY5Y, SK-N-AS, and the chemoresistant LA-N-6 cell line^.

Bortezomib: Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor that was tested in humans that degrades pro-apoptotic proteins such as p53. The role of bortezomib is to interrupt this process and resulting in the destruction of cancerous cells ¹¹.

Pharmacology: This agent is used for the treatment of multiple myeloma ¹¹.

Mode of Action: It is a proteasome inhibitor type drug. It removes excess protein and breaks down into its constituent parts so that the cell can reuse it. Proteasome inhibitors work in such a manner that it blocks the function of proteasome followed by the accumulation of protein in the cell, which becomes toxic to the cell and causes it to die. This is particularly important in myeloma cells as they make lots of proteins and so really rely on proteasome to function properly. Therapies targeting the proteasome can specifically kill myeloma cells rather than all of the cells in the body. Bortezomib being a reversible inhibitor in mammalian cells degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation) ¹¹.

Cell Lines Effect: From literature, it has been studied that bortezomib has effects on human breast cancer cell lines such as ANBL-6 BR, HCC 1937, MCF 7, MDA-MB-231, MDA-MB-468, SK-BR-3, BT-474 ²⁸.

Palbociclib: For the treatment of postmenopausal in women with estrogen receptor (ER)-positive; human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer an endocrine-based therapy for metastatic disease used which is an oral, selective, small-molecule inhibitor of CDK4 and CDK6 ^{11, 29, 35}.

Pharmacology: It is a combination drug with antiestrogens, letrozole for the treatment of breast cancer cell lines ^{11, 19}.

Mode of Action: Palbociclib is a kinase inhibitor drug where CDK4 and CDK6 along with their regulatory partner cyclin D1, play a key role in regulating the G1- to S-phase cell-cycle transition where regulation of the retinoblastoma (Rb) protein is phosphorylated ¹¹.

Cell Lines Effect: liver cancer cell lines, in-vitro, in ex-vivo HCC samples, in a genetically engineered mouse model of liver cancer and in human HCC xenografts in-vivo.

Pembrolizumab: Pembrolizumab commonly known as Keytruda, is a protein-based humanized monoclonal antibody used for treating Melanoma, Non-Small Cell Lung Cancer and Head and Neck Cancer by blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2 ^{8, 11, 44}.

Pharmacology: It is a protein-based humanized monoclonal antibody drug used for treating patients with metastatic melanoma ⁴⁴.

Mode of Action: Pembrolizumab acts as a checkpoint inhibitor where T lymphocyte plays a key role. Being an antibody-drug that targets the T-cell receptor of programmed cell death protein (PD-1) present on the cell surface, inhibits the binding of ligands (PD-L1 and PD-L2) of PD-1 ensued by inducing an antitumor immune response. Upregulation of PD-1 ligands is a mechanism for tumors to circumvent antitumor immune response ^{8, 34, 44}.

Cell Lines Effect: From the literature, it has been investigated that it shows effects on PD-1 cell line (host cell line-HEK293), M109 ^{6, 41}.

Rituxam (Rituximab): It is a recombinant DNA derived humanized monoclonal antibody. It recognizes CD20, a receptor found exclusively on the surface of both normal and malignant B lymphocytes ¹¹.

Pharmacology: Rituximab is used for treatment of CD20-positive non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. The antibody leads to selective killing of β-cells ^{23, 30}.

Mode of Action: Rituximab or Rituxan is recombinant DNA derive humanized monoclonal antibody used as therapy for treating a broad variety of β-cells malignancies. It recognizes a receptor named CD20 found on the surface of both normal cells and malignant cells. The function of the drug is to bind with the receptor CD20 and destroy the target cell. From various in vitro studies conducted suggest that Rituxan depletes circulating B-cells and reduces the size of B cell lymphomas in different ways. Various studies assert that this humanized monoclonal antibody drug kills B-cells through Complement Dependent Cytotoxicity (CDC) or Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) ⁴⁶.

Cell Lines Effect: From the literature, it has been investigated that it shows effects on NK-92; NK-92MI ^{6, 37}.

Lenalidomide: Revlimid or Lenalidomide is an immunomodulatory synergistic drug ¹¹.

Pharmacology: Lenalidomide is an anticancer drug having immunomodulatory and antiangio-genic properties that modify the immune system function and prevents the proliferation of blood vessels to treat patients with multiple myeloma (MM), transfusion-dependent anemia in myelo-dysplastic syndromes and mantle cell lymphoma ¹¹.

Mode of Action: Revlimid performs dual action of antitumor and an immunomodulatory effect. The tumoricidal effects of this anti-cancer drug induce cell cycle arrest, facilitates apoptosis of tumor cells, reduces angiogenesis, stromal cell support, and severance to the production factors that promotes myeloma cell survival and proliferation. Revlimid inhibits the cell cycle of myeloma cells by increasing the expression of tumor suppressor genes such as CDK inhibitors and the family of early growth response genes.

The up-regulation of these genes in the presence of Revlimid arrests the cell cycle and prevents the division of myeloma cells. It activates the effector proteins of apoptosis called caspases and facilitates the release of pro-apoptotic signals such as cytochrome C inside the cell that increases the sensitivity of tumor cell factors stimulating apoptosis that increases tumor cell death. In-vitro drug synergism study of Dexamethasone with Revlimid has shown enhanced tumor cell apoptosis; inhibition of angiogenesis to the tumor cells by reducing vascular endothelial growth factor and IL-6 levels. Revlimid inhibits the adhesion of myeloma cells to bone marrow stromal cells. The proposed immunomodulatory effect of Revlimid increases the activation and proliferation of various immune cells by facilitating interaction between antigen-presenting cells (APC) and T-cells. It also increases the expression of cytokines that control the proliferation, differentiation, and survival of various immune cells that release cytokines which further stimulates immune cell proliferation that activates T-cells and NK cells activity leading to increased activity against myeloma cells causing them to undergo apoptosis ¹¹.

Cell Lines Effect: Studies from the literature shows that Revlimid has been examined on these human MM-cell lines such as MM.1S, INA-6, RPMI-8226, MM.1R, KMS12PE, and U266 individually or in combination with other drugs ⁶.

Letrozole: It is an oral non –steroidal aromatase inhibitor introduced for the adjuvant treatment of hormonally-responsive breast cancer ¹¹.

Pharmacology: Aromatase inhibitors inhibit the action of the aromatase, an enzyme which converts androgens into estrogens by a process called aromatization to treat breast cancer ¹¹.

Mode of Action: Aging declines the production of ovarian estrogen. Therefore, to convert adrenal androgens to estrone and estradiol after post-menopause aromatase enzyme plays a significant role. Aromatase catalyzes the rate-limiting step in estrogen biosynthesis.

Letrozole is an enzyme inhibitor drug that inhibits the conversion of androgens to estrogens by competitive inhibition. Binding to the heme of the cytochrome P450 subunit of the aromatase enzyme results in the reduction of estrogen biosynthesis in all tissues. Women treated with letrozole significantly lowers serum estrone, estradiol, and estrone sulfate ^{11, 20, 31}.

Cell Lines Effect: From literature, the study has shown that letrozole-treated cell lines are MCF-7, AC1, T47D ⁴⁷.

Progression-Free Survival Analysis of Different Treatments:

TABLE 2: PROGRESSION FREE SURVIVAL STUDY AND STATUS OF TREATMENTS

*PPC (Pembrolizumab, pemetrexed and carboplatin chemotherapy); *PC (Pemetrexed and Carboplatin), chemotherapy and Pembrolizumab; *R-CHOP (Rituximab Cyclophosphamide Hydroxydaunomycin Oncovin ® Prednisolone); *CHOP; GM-CSF (Granulocyte macrophage colony-stimulating factor); *Panobinostat plus bortezomib & dexamethasome (PAN-BTZ-Dex); *Placebo plus bortezomib & dexamethasone (Pbo-BTZ-Dex); *Ixazomib & Lenalidomide – dexamethasone (IRd); *Lenalidomide- dexamethasone (Rd); *Folinic acid, fluorouracil and oxaliplatin (FOLFOX)

DISCUSSION AND CONCLUSION: This review article concentrated on different cancer cell lines worked on with newly FDA approved anticancer drugs as therapy; antibody engineering, their efficacy as treatment followed by the status of the treatment.

Lately, an emerging technology antibody engineering holding the copious scope in the treatment of cancer providing new types of antibodies from the bench to the bedside by decreasing immunogenicity, transforming half-life, enhancing efficacy, and increasing tumor-targeting. The first segment of the paper has an accumulation of different cancer cell lines with their histotype, morphology in a tabular manner from various databases, cell line banks, followed by newly FDA approved engineered mAbs showing their effect on different anticancer drugs with their mode of action and pharmacology. Later in tabularly form, the progression-free survival (PFS) rate and the status of treatment of the anticancer drugs alone or combined with others.

ACKNOWLEDGEMENT: The authors express ardent gratitude towards the Department of Biotechnology, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Panihati, Kolkata - 700114, West Bengal, for rendering constant assistance while writing this review.

CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

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    How to cite this article:

    Roy C and Chakraborty T: A review on translational perspective and efficacy of different engineered therapeutic antibodies. Int J Pharm Sci & Res 2020; 11(6): 2604-16. doi: 10.13040/IJPSR.0975-8232.11(6).2604-16.

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