Cytotoxic drugs used in the treatment of solid tumors and hematological malignancies have, over the last 50 years, changed the natural progression of these diseases [1]. However, the non-specificity as well as the extreme toxicity of some of these drugs may also limit their usability, and have, in some cases, have lead to discontinuation of these compounds.

This scenario has caused researchers around the world to search for and develop therapeutics that can overcome these limitations. Among the drugs they have developed, are antibody-drug conjugates or ADCs.

Antibody-drug Conjugates combine the unique targeting capabilities of monoclonal antibodies (mAbs) with the specific cancer killing ability of cytotoxic drugs. By attaching biologically active chemotherapeutic drugs, radioactive isotopes, cytokines or cytotoxins via chemical linkers with liable bonds to a monoclonal antibody directed to antigens differentially overexpressed in tumor cells, ADCs significantly improve sensitive discrimination between healthy and diseased tissue. Anitibody-drug Conjugates are part of a specialized subset of highly potent active pharmaceutical ingredients (APIs).

Over the past decade pharmaceutical companies have started to commercialize antibody-drug conjugates. Today, about 50 molecules are in clinical development. Of these, approximately 25% are in Phase II or Phase III of development, leading to a rapidly expanding pre-clinical pipeline. With nearly 190+ active clinical trials, antibody-drug conjugates are gaining acceptance across the globe as they offer superior pharmacological efficiency along with minimized side effects.

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Superior clinical results
Most of the success has been found in areas of oncology and hematology where they have been able to produce superior pharmacological clinical results as compared to other cancer therapeutics available in the market. In the coming years ADCs are also expected to be introduced for the treatment of other therapeutic areas due to which their market shares are expected to increase. For example, earlier this year Seattle Genetics, started a clinical trial of brentuximab vedotin (also known as SGN-035; Adcetris®) in the treatment of systemic lupus erythematosus,  a chronic autoimmune rheumatic disease in which the body’s own immune system, overreacts, creating autoantibodies and other autoimmune responses that attack multiple healthy organs, causing inflammation, pain and permanent organ damage. [2]

However, research and development of ADC has gained lots of attention due to their capability to treat various cancers. Since the early 2000’s three Antibody-drug Conjugates have been approved.

Development of ADC
The complex development of ADCs has been possible based on improvements in monoclonal antibody engineering and production, combined with advances in potent cytotoxic drug synthesis and selection, development of more stable linker chemistry and conjugation methods. These developments are likely to ensure that the next generation ADCs have a fastly improved safety/efficacy profile.

These improvements have resulted in a large number of ADC drug-candidates entering the preclinical development pipeline. However, despite the progress, successful clinical application has been difficult and slow – and of the three ADCs who have received U.S. Food and Drug Administration (FDA) approval, only two are currently in the clinic, including brentuximab vedotin and ado-trastuzumab emtansine (also known as T-DM1; Kadcyla®; Genentech/Roche). In 2010 gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories) was discontinued due to adverse events, but clinical trials with this drug are, since then, ongoing.

Today, the most commonly used cytotoxins in antibody-drug conjugates in (pre-)clinical development include auristatins (MMAE and MMAF), calicheamicin, maytansine and duocarmycin. Auristatin dominates the market and accounts for over 50% of ADCs in clinical development.

Novel approaches
Solid cancers, including lung cancer, breast cancer, ovarian cancer have high patient base. Only a limited number antibody-drug conjugates have shown efficacy in while others, due to limited number of receptors on the cell surface, have not shown efficacy.

In solid cancers,  HER2 is a target for the development of an number of ADCs. For example, The Netherlands Synthon believes that their investigational drug SYD985 has the potential to at least double the current breast cancer population eligible for HER2-based ADC treatment. If successful, SYD985 may provide new treatment options for patients with a high unmet medical need, including triple negative breast cancer. Furthermore, other targets, including  Epidermal Growth Factor Receptor Variant III (EGFRVIII), are being explored for the treatment brain cancer.

To increase efficacy, researchers are developing a new approach in which chemically triggered release of drug from ADC is being studies.  To date, this type of antibody-drug conjugate is approved by regulatory agencies, hence market researchers believe that this segment has significant marketing opportunities.

In contrast to antibody-drug conjugates for the treatment of solid cancers, the pipeline of ADCs for hematological malignancies is quite strong.  With more antigens over-expressed in hematological malignancies as compared to other malignancies, investigators are expecially interested in CD19, CD22, CD25, CD30, CD33 for an array of disease, including Hodgkin lymphoma (HL), Non-Hodgkin’s lymphoma (NHL), and Anaplastic Large Cell Lymphoma (ALCL).

Investigators developing a number of antibody-drug conjugates for the treatment of malignancies like, prostate cancer, kidney cancer, lung cancer and other cancers.  Many of these trial drugs are currently investigated in clinical trials. In the next 5 years, investigators expect that they will be able to find more targets directly – or only – associated with specific malignancies.  If their expectations are realized, the market market size of ADCs may increase several folds in coming years.

In order to be effective naked, unconjugated, therapeutic monoclonal antibodies or TMAs used in the treatment of human disease, require significant quantities as well as multiple treatments. Clinical evidence shows that antibody-drug conjugates require a lower doses to be effective.

Both naked antibodies as well as antibody-drug conjugates are approved for manufacture in mammalian expression and bioreactor systems, which require expensive upstream and downstream processes. In addition, the production of antibody-drug conjugates involves additional, specialized, technologies – including chemical conjugation steps – complicating production streams. These factors result in the outsourcing of 70%-80% of all ADC manufacturing to a limited number of specialized contract manufacturers or CMOs capable of manufacturing monoclonal antibodies, linkers and cytotoxins. In addition, even fewer CMOs have the ability to provide specific conjugation services required to manufacture the actual ADC.[3]

Global Market Growth
The Global Antibody Drug Conjugate Market & Pipeline Insight 2020 report, published by P&S Market Research, highlights the development of the global market of antibody-drug conjugates, discusses the mechanism of action of a number of ADCs as well as their indication and future prospects. [4]

The report further covers various aspects, discussing advantages of antibody drug conjugates over traditional antibody therapeutics, the need for this new class of medicine, manufacturing challenges, key market drivers and upcoming opportunities. The key objectives of the report is to help readers understand the current and future state of the antibody-drug conjugates market. The authors accomplish this by analyzing antibody-drug conjugates currently available in the market and drug candidates in pre-clinical development as well as reviewing the technology including key cytotoxin, linker and conjugation technologies supporting the development of improved ADCs. [4]

Based on therapeutic area, next-generation antibody therapeutics market is expected to see faster growth during the forecast period of 2015-2020. Basis on the technology, the next-generation antibody therapeutics market can be segmented as antibody-drug conjugates, bispecific antibodies, Fc-engineered antibodies, antibody fragments and antibody-like proteins.

As a result of high potential of ADC technology, the authors of the report, healthcare providers are specifically using novel ADC technology for the development of next-generation antibody therapeutics for the treatment of solid cancers and hematological malignancies.  Give the unique characteristics of these ‘loaded antibodies’ the authors of the report showed that the ADCs market increased at a CAGR of approximately 87.2% during 2011-2014. As a result, the growth of this market also boosted the market for next-generation antibody therapeutics during the period. [4]

The editors further write that the global next-generation antibody therapeutics market, valued at $1,490.0 million in 2014, is expected to grow at a CAGR of 20.9% during the period 2015 – 2020. This includes an accelerated growth of the ADC market. According to the authors, the global next-generation antibody therapeutics market is increasing due to growing global R&D activities – which is evidenced by the increasing number of companies engaged in R&D for new improved next-generation antibody therapeutics, including ADCs.[4]

With around 7-10 new commercial ADC launches expected over the coming decade, the authors of the report conclude that, going beyond 2020, the global antibody-drug market will, after 2024, be worth more than US $10 billion annually. [4]


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