With our increasing understanding of disease mechanisms and our ability to unlock the power of the immune system to break significant barriers and change the standard of care for patients with cancer or hematological malignancies, analysts predict that the future of healthcare lies in expanding the clinical benefit of novel, targeted, therapeutics to a larger proportions of patients.
Among these novel therapies are antibody-drug conjugates or ADCs, which have, over the last decade, taken cancer treatment to a new level. Antibody-drug conjugates – and many other candidate biologics in clinical trials – are distinctly different from ‘simple’ recombinant proteins. Based on increased global investments, and the expectation that ADCs may ultimately extend beyond cancer and hematological malignancies, the outlook for the next few years is optimistic.
However, the development and manufacturing of these novel, high potent agents and advanced next-generation targeted therapies, require significant advances in biomanufacturing technologies and more advanced characterization methods – during manufacturing – to identify and remove contaminants.
In developing these new highly potent drugs, manufacturing scientists are continuously challenged to develop specific analytical methods to accurately determine the physico-chemical and structural properties, purity, potential contaminations and impurities, quality, biological activity and therapeutic properties. Overall, these challenges range from chemistry to analytics and from processing to formulation 
As part of the manufacturing process, advanced analytics and ADC-specific assays are required for batch comparability and toxicity detection. Furthermore, process optimization and scaling-up are critical to ensure a smooth transition from initial clinical to commercial phase, while dosage and formulation hold the key to patient safety and efficacy.
Although there are currently no specific guidelines targeting antibody-drug conjugates, regulatory agencies, including the European Medicines Agency (EMA) require monoclonal antibody-based products (including ADCs) to be thoroughly characterized. The European guidelines addresses quality issues for the marketing authorization of monoclonal antibodies intended for therapeutic or prophylactic use (including ex vivo application), and in vivo diagnostic use.
Furthermore, the International Conference on Harmonization (ICH) guidelines provide a uniform set of internationally adopted principles for the characterization of these novel agents.
|Structural Characterization||Physico-chemical Analysis|
|Amino acid sequence||Molecular weight or seize|
|Amino acid composition||Isoform pattern|
|Terminal amino acid sequence||Extinction coefficient (or molar absorptivity)|
|Peptide map||Electrophoretic patterns|
|Sulphydryl group(s) and disulfide bridges||Liquid Chromatographic patterns|
|Carbohydrate structure||Spectroscopic profiles|
Based on the growing number of novel biologics drug candidates, changing expectations in the characterization of ADCs are driving improvement in the development of analytical equipment as well as the development of novel systems and processes.
Growing number of ADCs
According to the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents the country’s leading biopharmaceutical researchers and biotechnology companies, there have, to date, been three ADCs approved, including Gemtuzumab Ogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories; withdraw from the market in 2010), Ado-trastuzumab Emtansine, also know as T-DM1 (Kadcyla®; Genentech/Roche) and Brentuximab Vedotin (also known as SGN-035; Adcetris® by Seattle Genetics) and nearly 50 investigational ADCs are progressing in more than 300 in clinical trials.
In early 2016, Immunomedics’ investigational ADC, Sacituzumab Govitecan, also known as IMMU-132, in development for the treatment of triple-negative breast cancer (TNBC), was awarded breakthrough therapy designation by the U.S. Food and Drug Administration (FDA).
In May 2016, Abbvie spent US $ 5.8 billion to buy Stemcentrx to get its hands on rovalpituzumab tesirine, also known as Rova-T, a novel biomarker-specific ADC-therapy that is derived from cancer stem cells and targets delta-like protein 3 (DLL3) that is expressed in more than 80% of Small Cell Lung Cancer (SCLC) patient tumors and is not present in healthy tissue. The investigational drug combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.
In Phase I/II studies of relapsed SCLC patients who have previously failed one or more standard therapies, rovalpituzumab tesirine demonstrated overall response rates of 44% in the patients identified with high expression of DLL3. The expression of DLL3 suggests rovalpituzumab tesirine may also be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme, prostate, pancreatic and colorectal cancers, where DLL3 expression ranges from 50-80%.
Clinical data for two other ADCs being developed by Astellas and Seattle Genetics, ASG-15ME and Enfortumab vedotin, also known as ASG-22ME and ASG-22M6E, were presented at the American Society of Clinical Oncology‘s (ASCO) 51st Annual Meeting held June 3-7, 2016, in Chicago, IL, showing strong clinical activity of these two novel ADCs.*
The development of ADC has taken flight. In the “2016 Nice Insight CDMO Outsourcing Survey” responding companies said that they have biologic drugs in their pipelines: 57% are developing ADCs compared to 51% with ‘naked’ mAbs under evaluation.
In earlier reports, Nice Insight highlighted a number of trends driving the growth and structure of the biopharmaceutical market. With the ability to address more complex diseases with novel, advanced, therapeutics, including antibody-drug conjugates, developing and manufacturing becomes more challenging – and more costly. At the same time, payers are looking for ways to reduce the costs of therapies or find proper justification for treatments exceeding US $ 150,000 per patient per annum.
Other targeted therapies
In addition to developing antibody-drug conjugates, a number of biotechnology companies are developing promising gene and cell-based therapies (e.g., chimeric antigen receptor T-cell (CAR-T) for the treatment of a broad range of cancers.
These CAR-T cells combine an antigen recognition domain of an antibody with the intracellular signaling domain into a single chimeric protein.
Specific blockade of the PD-1 immunosuppressive pathway can significantly enhance the function of gene-modified T cells expressing a chimeric antigen receptor (CAR) leading to enhanced tumor eradication.  CAR T cell therapy in combination with PD-1 blockade overcomes PD-L1+ tumor immunosuppression, thereby leading to improved therapeutic efficacy. These novel treatments are designed to allow the immune system to recognize and attack malignant cells as it would any other intruder. 
Many of these novel drugs, showing long term remission in some patients, are current in clinical trials. One example of an FDA-approved treatment is pembrolizumab (Keytruda®; Merck Oncology/Merck Sharp & Dome Corp/MSD), a first among immune-oncology drugs aimed at unlashing the human immune system against various cancer and hematological malignancies.
Although most analysts agree that the immuno-oncology era is off to a promising start, there are substantial obstacles to further clinical and commercial success. Among these obstacles are the large number of companies involved in the development of immune-oncology drugs.
According to a Tufts Center for the Study of Drug Development Impact Report published in March 2016 by Tufts University, more than 130 biotech and 20 pharma companies are developing immune-oncology therapies. This activity reflects—and is fueling—worldwide immune-oncology product sales, with annual revenues expected to reach $25 billion to $40 billion by 2020, up from $2.5 billion in 2015.
Other obstacles include developers identifying validated biomarkers to increase the likelihood of clinical success and reduce development time and cost, the growing difficulty of recruiting enough volunteers for clinical trials (on average less than 5% of cancer patients in the US participate in these trials), and cost-benefit metrics payers may adopt to guide reimbursement, which could limit market access and possibly healthy returns to investors.
The global market for biopharmaceuticals, in 2014 valued at US $ 162 billion, is, according to Persistence Market Research (PMR), an innovative and specialized supplier of market intelligence reports and consulting services, expected to grow at a compounded annual growth rate (CAGR) of 9.4% to reach US $ 278 billion in 2020.  A previous PMR report showed that among different product segments, antibodies-based products are the largest, accounting for an estimated share of 25.6% in 2013, equating to US $ 51.1 billion.
Analysis shows that this market growth is primarily the result of an aging population and a more effective – personalized, targeted and precision – treatments with biologics (more effective than treatment with small molecule medicines). However, the growing costs of developing and manufacturing biopharmaceuticals has, over the last decade, increased the pressure to reduce expenses. This pressure is, according to many analysts, also expected to restrain market growth.
The emergence of personalized medicine has resulted in an increased demand of smaller-volume products and the need for a more flexible manufacturing approach. Combined with the a response to the pressures of cost containment, manufacturers are installing new, state-of-the-art, small-volume manufacturing capabilities based on single-use technology. These systems are supplied by companies including Sartorius Stedim Biotech, Entegris Life Sciences, Thermo Fisher Scientific, MilliporeSigma, Pall Life Sciences and others, offer scalability (from lab scale to commercial manufacturing) for flexible manufacturing of antibody-drug conjugates and other biologics.
The the current Good Manufacturing Practice (cGMPs) regulation for human pharmaceuticals manufacturing requires that facilities must be designed to handle both biological species and highly potent cytotoxic small organic molecule drugs. This also applies to single-use manufacturing technology.
Today, single-use technologies are widely used by small biotech firms for (initial) process development and small volume clinical-scale manufacturing for late-stage clinical trials. But larger manufacturers are now also adopting single-use technology to meet expanded demand for new products more quickly.
Since the benefits of single-use technologies include the reduction in upfront capital costs of establishing traditional, stainless-steel, manufacturing facilities and reducing operating costs (various estimates show a reduction in capital costs of 40 – 50% and lower operational costs of 20 – 30%), they are increasingly employed in newer flexible manufacturing facilities. Furthermore, it reduced the requirement for traditional utilities such as clean-in-place reagents, water for injections and clean steam for equipment sterilization. Overall, these flexible systems allow greater design flexibility than traditional stainless steel equipment, enabling changes to be made quickly in order to select flexible – optimum – processing configurations during development and scale-up.  As such, the adoption of single-use technology reduces cleaning and changeover times between various manufacturing campaigns.
However, some experts feel that, unless the industry moves towards a ‘health-based risk assessment’ approach to single-use technologies, innovation could be compromised – particularly for novel agents like antibody-drug conjugates. They believe that problem for a number of novel biologics is that single-use facilities may increasing the costs of development and, as a result, are putting promising novel agents at risk when they are deemed unviable before their true potential has been explored. 
According to a HighTech Business Decisions‘ report about Fill-and-Finish published in December 2015, the market for biopharmaceutical contract fill-and-finish services has grown at a compound annual rate of 17% over the past three years. HighTech’s analyst expect that this market will continue to expand and reach US $ 2.4 billion in 2020. Furthermore, executives from contract manufacturing organizations expect future annual market growth of 15% per year. Driving this growth for fill-and-finish services is the demand for biotechnology drugs, investment in biotechnology projects, and new service offerings. Manufacturers continues to rely on fill-and-finish CMOs to provide filling and lyophilization capacity for both its commercial- and clinical-phase drug product production.
From a strategic side, analysts expect more industry consolidations over the next few years, new market entrants, and greater in-house fill capacity. As a result of these trends, they expect industry capacity utilization rates will remain flat.[1o]
Mergers and acquisitions
In a recent report, Nice Insight analysts also predicted an increase in the number of mergers and acquisitions. Their prediction comes on top of the 2014 and 2015 boom years in which the number of initial public offerings and mergers and acquisitions of biotechnology companies reached historic highs. Furthermore, licensing activities in many therapeutic areas, including in oncology and hematology, were up sharply compared to previous years.
One of the observed reasons behind this trend is the strategic shift in which many biotech companies are outsourcing innovative R&D to biopharmaceutical contract development and manufacturing organizations (CDMOs) and academic partners. This new approach, no doubt, is a paradigm shift challenging existing ideas of business development in the biotechnology and pharmaceutical industry. 
Today, the biopharmaceutical contract manufacturing (CMO) and contract development and manufacturing (CDMO) sector is fairly fragmented with a large number of players. US-based market research company HighTech Business Decisions has identified more than 500 companies claiming to be a CMO or CDMO.  And while only a handful of these companies have the capability required to manufacture recombinant proteins and high potent agents like antibody-drug conjugates, one of the observed trends is that drug developing biopharmaceutical companies are not just looking for cost-savings when turning to a CMO/CDMO. According to a report published by Roots Analysis, the most important drives is the need for technical expertise, operational efficiency, regulatory support and the ability to focus on core competencies. 
Given the current market – and strong growth, it should not be surprising to see an increase in consolidation. One of the most notable in 2016 was the initial attempt by Swiss specialty chemicals and life sciences company Lonza, which has a market capitalization of 8.7 billion Swiss Francs (US $ 9 billion), to acquire US drug delivery technology company Catalent. While Lonza and Catalent have, so far, not agreed on a price, and there is no certainty that negotiation will continue, this initial attempt confirms that 2016 is again an interesting year.
Although not all activities involved companies involved in the development of antibody-drug conjugates, mayor mergers in the last few years have included the mergers of Cambridge Major Laboratories with AAIPharma (forming a new company called Alcami) and Pantheon and (Royal) DSM Pharmaceutical Products (with the subsequent acquisition of DPx Holdings of Gallus Biopharmaceuticals). Furthermore, acquisitions have included the acquisition of Hospira, a leading provider of injectable drugs and infusion technologies, by Pfizer and more recently, Germany-based Merck KGaA‘s acquisition of Sigma Aldrich (forming Merck KGaA’s new business unit MerckSigma).
Discussions with experts during the Bio International Convention clearly confirm the excitement felt in the industry – among scientists, researchers and industry leaders – and reveal the potential to really revolutionize – accelerate drug development, manufacturing and healthcare.
In 2017 the Bio International Convention will be held June 19 – 22 in San Diego, CA.
This article is based on interviews conducted during the Bio International Convention held June 6-9, 2016 in San Francisco, CA.
* For an overview of clinical data of antibody-drug conjugates presented during the 2016 annual meeting of the American Society of Clinical Oncology, click here.