The Significance Of Biotechnology MABs

Introduction

Human health is one of the greatest growing global concerns. Biotechnology has played a dynamic role in successfully improving human health challenges through implementation of promising technologies (Afzal et al., 2016). Medical biotechnology has come into public light since the existence of genetics. Including the discovery of DNA by Watson and Crick in 1953, to recombinant DNA techniques by Cohen and Boyer in 1973, via splicing of DNA strands from Escherichia coli (E. coli) into DNA of another. Thereby, establishing genetic engineering and basis of new biotechnology which is defined as the focussing of industrial use of recombinant DNA, bioprocessing and cell fusion techniques (Waseda University, n.d.).

With increasing human populations, industrialisation and poor advancements in climate and healthcare, many diseases have prevailed and cannot be overcome using conventional therapeutics. Disease management has been a pandemic concern since the early 1900s; in England and Wales a sample of 123,000 deaths in the Registrar-General displayed that 91% of these mentioned onset of diabetes (Stocks, 1944). The International Diabetes Federation (IDF) estimates a total of 415 million living with diabetes in 2015, expected to rise to 642 million by 2040 (Mbanya et al., 2017). Furthermore, Cancer has been a leading medical concern, evident from a 25% increase in mortality rate between 1900 to 1913. This escalated to 1,735,350 new cases in 2018 in United States alone from which 609,640 died (NIH, 2018). The continuing impact of diabetes and cancer on public health depicts the need to improve and implement new biotech-therapies to treat the increasing diseased population.

Modern biotechnology has replaced conventional diagnostic tools that are inaccurate, laborious, time consuming and expensive. Novel molecular diagnostic tools draw advances in biology for disease control. The University of Toronto has ranked molecular diagnostics as the most ideal set of technologies for improving public health (Afzal et al., 2016). A promising novel-therapeutic is monoclonal antibodies (MAbs). These are the ultimate precision medicine that can selectively target tumour cells and T-lymphocytes via antigen recognition for diabetes and cancer treatment (American Cancer Society, 2015).

This essay aims to evaluate the evolution of biotechnology techniques for diabetes and cancer, and the need for MAb therapy as an alternative replacement technique.

Thus, the research question for this essay is: Can MAb therapy be used to replace current diabetic and cancer therapeutics?

Impact of biotechnology in diabetes and cancer

Biotechnology in diabetes

Earlier diabetic therapies were effective but unethical, demonstrating a need for novel biotechnology treatments. During 1906-1916, insulin was obtained from pigs and cattle pancreas via ‘injecting-dogs-with-their-own-juice’ (McClathey, n.d.). Ganz et al. (1990), reported that using insulin from animals causes the human body to produce anti-insulin antibodies resulting in spontaneous hypoglycaemia. Investigating a 53-year old diabetic patient, they found that the onset of insulin resistance and systemic allergy initiated several months after receiving mixed beef-pork insulin. Suggesting that traditional insulin therapy was less-effective due to immunological rejection within patients. Furthermore, insulin derived from pigs causes major social concerns as it is religiously unacceptable to use for Jewish and Muslim population and using cattle for Hindus. This restricted global application of insulin therapy (Ogden, 2016). Thus, amended immunoregulatory biotech-procedures are required which meet ethical standards.

Overtime, recombinant DNA technology replaced animal-insulin. Genentech. (1978), inserted synthetic genes carrying genetic code for insulin, into E. coli. Once inside the bacteria, the genes are ‘switched-on’ and translates the code into ‘A’ or ‘B’ protein chains found in insulin. The chains are fused to construct insulin molecules, harvested and purified for use. The efficacy of recombinant insulin was confirmed by Weinges et al. (1981). They analysed the biological effect of biosynthetic human insulin (BHI) and purified pork insulin (PPI). BHI lowered blood glucose faster during the first 30 minutes and caused a greater drop-in plasma glucose after 60 minutes, 44.3% for BHI and 40% for PPI. Highlighting the effectiveness of recombinant technology for hyperglycaemia. Thereby, appraising the positive impact of biotechnology in the diabetic industry.

However, recombinant therapy is not sustainable for long-term application. Baeshen et al. (2014), stated that with the global rise in diabetic patients, insulin requirement will increase by 16,000 kg/ year, and current expression systems would not suffice future demands. Also, the disadvantages of using E. coli expression system include; loss of plasmid property, endotoxin contamination etc. Therefore, new therapeutics are required over recombinant insulin which possibly focuses on immune system specificity and interfering with lymphocyte activation.

Biotechnology in Cancer

Current cancer therapies include chemotherapy and radiotherapy (RT). However, these techniques have a low remission rate with minor contribution to cancer survival. This was supported by literature searches reporting a 5-year survival attributable to chemotherapy in 22 malignancies, from cancer registry data in Australia and surveillance Epidemiology in USA. They found that chemotherapy survival was 2.3% in Australia and 2.1% in USA. This clarifies that chemotherapy has limited impact on cancer survival, further emphasizing need for new biotech-techniques to treat the rising cancer cases (Morgan, Ward and Barton, 2004).

Although, Initial chemotherapy like aminopterin which blocks function of folate-requiring enzymes, crucial for DNA metabolism caused remission in children with acute leukaemia. Today, 85% of children diagnosed with leukaemia are cured using chemotherapy. Thus, chemotherapy exists as a primary cancer therapeutic, until more efficient technology can replace this (American Cancer Society, 2014). Additionally, Yarana and Clair. (2017), found that chemotherapy was toxic to normal cells: from 215 cancer drugs approved by Food and Drug administration, 50% induce oxidative stress reaching the threshold of antioxidant capacity of cells. Accumulation of oxidative molecules alters cells quality leading to cytotoxicity in normal cells and elevates risk of developing a new primary cancer. Hence, more specific, tumour targeting therapies need to be engineered.

Regarding RT, the scenario of ionising beam particles in medicine changed after x-rays were discovered in 1953. RT acts through direct DNA damage (particulate) or indirect cell damage after production of free radicals (electromagnetic) (Gianfaldoni et al., 2017). Biotechnology has drastically improved RT; initially administered as simple beams with minimal imaging guidance. Currently delivering highly targeted imaging treatments with intensity modulated RT (IMRT) allowing maximum cancer control. Beyond 50% of patients require RT during malignant tumour treatment. Implying that RT is a success complimentary cancer management therapeutic (Thompson et al., 2018).

However, RT utilises high-energy radio-waves which affects normal tissue cell division, stimulating unwanted side-effects and lowers RT remission rate (40-60%) dependent on cancer type (Kirby, 2011). Successful RT treatment needs to balance between destroying malignant cells and minimising non-cancerous cell damage (American Cancer Society, 2016). Also, the addition of chemotherapy increases cell toxicity by 300% (Bath, 2017). Indicating that conventional cancer therapies are not reliable diagnosis and targeted therapeutics associated with fewer side-effects are necessary.

Impact of Biotechnology on Monoclonal Antibody (MAb) Production

Development of MAb

Biotechnology can transform the ideology to acquire immunity to diseases into a therapeutic intervention seen through MAb production. These are generated by identical immune cells that are cloned from single parent cells. They have a monovalent affinity, therefore bind to the same epitope of an antigen inducing antigen destruction or neutralising pernicious actions caused to the body (Liu, 2014).

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Development of MAb technology

Köhler and Milstein originally engineered MAbs using stable cell lines known as hybridomas. Hybridomas are generated by fusing B-lymphocytes with murine myeloma cell line (absence of hypoxanthine-guanine-phosphoribosyltransferase gene). These are cultured in vitro in selective media where only hybridoma survive, and then injected into abdomen of another mouse (ascite method) or cultured in flasks and bioreactors to produce large quantities of MAb (Liu, 2014).

Following the hybridoma technique, combined with analytical tools including fluorescence-activated cell sorting (FACS), MAbs were used to inspect the surface structure of cancer cells, to identify cancer-antigens. This led to the discovery of the first murine antibody Orthoclone (muromab) OKT3, against T-lymphocytes to prevent host versus graft reaction during kidney transplantation (Scott, Allison and Wolchok, 2012). However, this method was discouraged by Echko and Dozier. (2010), as an unethical technique. Ascites method causes pain and distress to animals, and this process is slow and laborious. Therefore, governments in Australia, Netherlands, Germany, Switzerland and United Kingdom have banned in favour of such in vitro techniques.

Fortunately, a more effective method exists using recombinant biotechnology; recombinant antibodies (rAbs), created using synthetic genes. This involves cloning antibody genes into high-yield expression vectors which are re-introduced into host (Abcam, 2019).

This technique has increased reproducibility and control over hybridoma. Researchers lose control after injecting antigens into animals as they may be processed differently or sliced into particulates and antibodies could be generated against these altered antigens. Whereas, with rAb, researchers can favour antibody isolation against antigen by adjusting experimental conditions. Therefore, recombinant technology has led to increased precision, control and reliability of therapeutics. Production time is also lower for rAb, 8 weeks whereas hybridoma requires 4 months. Implying biotechnology has modernised medical-therapeutics to treat diseases more efficiently (G-Biosciences, 2015).

MAbs over Chemotherapy

The addition of serological testing with hybridoma technology has led to cancer specific MAbs. These target cell surface receptors, activates antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). MAbs have specific affinity to cancer cell receptors compared to conventional therapies demonstrated as non-specific causing normal cell cytotoxicity (Scott, Allison and Wolchok, 2012).

For example, humanized MAb Herceptin (trastazumab) is used to successfully treat metastatic breast or gastric cancer for patients overexpressing Her2 receptor. The was experimented by Bang et al. (2010), by introducing 584 patients with gastro-oesophageal cancer to trastazumab plus chemotherapy and chemotherapy alone to investigate cancer survival rates. They found trastazumab increases overall and median survival rate by almost 3 months even for comparator group. Also, trastazumab did not increase toxic effects usually associated with fluoropyrimidine-based or platinum-based chemotherapy. Demonstrating trastazumab is a clinically significant therapeutic over conventional chemotherapy alone.

Consequences associated with MAb involves large-scale production costs. Various studies show MAbs need to be injected in high doses, 6–12g per patient for Rituximab (Chames et al., 2009). Production of MAbs uses large cultures of mammalian cells proceeded by extensive purification techniques, under good manufacturing practices for commercial viability, leading to extremely high production costs. The standard price of MAb is $96,731, with average treatment exceeding $100,000 for 32% of 107 MAb- indication combinations between 1997-2016. Whilst, they may be the future of therapeutics, MAb implementation for industry is limited by production costs (Hernandez et al., 2018).

However, recently government funding towards cancer research and biotechnology development has increased which can be used to manufacture MAbs. Also, Sharbaf et al. (2013), explained that the actions of MAbs could be amplified. They used genomic amplification with methotrexate (MTX) to increase population of cells expressing high levels of rAbs. Increasing gene copy number (3x) increased the protein expression levels up to 1000 times, and these could be used to generate MAbs with similar biological action as trastazumab. This reinforces the advancements in biotechnology and that MAbs are economically viable which can bring about greater reduction in cancer remission.

MAb over Insulin Therapy

MAbs target insulin receptors (INSR) located on liver, muscle and fat cell surfaces. Bi-allelic loss-of-function in INSR gene causes insulin resistance and early mortality. Bhaskar et al. (2012), developed MAb (XMetA) using phage display technology targeting INSR. In an insulin resistant model of diabetes, XMetA reduced elevated fasting blood glucose and glucose tolerance was normalized. Following 6-week treatment, improvements in HbA1c was observed. Demonstrating the positive impact of biotechnology in developing long-lasting agents for hyperglycaemic regulations without the invasiveness of an insulin injection.

Utilising this ideology, Prof. Mandelboim developed MAb (BL_9020) targeting NKp46 receptor which almost completely prevented diabetes in mice models. As NKp46 receptor recognise beta cells leading to their destruction. The university signed with BioLineRx, who entered collaboration with JHL Biotech in 2014 for development and commercialisation of BL_9020 in China and Southeast Asia. If replicated in humans, this technology could delay and prevent need for chronic insulin for 30 million people worldwide (ScienceDaily, 2015).

Herold et al. (2002), support the use of MAbs to treat type-1 diabetes over insulin therapy. They experimented effects of non-activating MAbs against CD3-hOKT3gamma1 (Ala-Ala) on the loss of insulin production. After 6 weeks of diagnosis, 24 patients anonymously received either a 14-day course of MAb or no antibody and were studied for a year. They found that MAb treatment improved insulin production in 9/12 patients compared to control group. Treatment effect using MAb lasted 12 months after diagnosis; glycosylated haemoglobin and insulin doses were reduced. Therefore, MAbs against CD3 could reverse hyperglycaemia and induce tolerance to recurrent diseases.

However, the scale-up from a lab to industry is a major concern for MAb feasibility. Commercial MAb production requires quality control and assurance departments to meet commercial requirements for good manufacturing practices, product-lot trials ensuring product reproducibility and process verification for consumer protection. In large-scale production ascites method is used in US, but this is illegal across the world making MAbs more expensive and unaccepted. Problems with in vitro techniques are; material, equipment, labour costs and is time consuming compared to in vivo which only takes 6 weeks. Another expense factor for biotech-techniques is requirement for trained employees with technical knowledge. Hence, multiple issues persist with industrial scale-up of MAbs (Ward et al., 1999).

Advancement of biotechnology with MAb

Overtime, MAb with T cell cytotoxicity and memory functions can be employed to develop better precision medicine; chimeric antigen receptor (CAR) T-cell therapy. This involves the genetic modification of patient T-cells via viral-based gene transfer or DNA transposons and direct transfer of transcribed-mRNA through electroporation, to produce CARs on the surface of cells. CAR-T cells could eliminate cancer cells and persist in the body for months, resulting in long-term cancer remission (Juno Therapeutics, 2019). Miliotou and papadopoulou (2018), showed promising results using CAR-T cells with a complete recover of 92% of end stage acute lymphocytic leukaemia. Indicating that CAR-T cell therapy could be the future diagnosis for cancer treatment and modified to target INSR.