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REVIEW
Realizing the Potential of Monoclonal Antibodies
William R. Strohl
VP, Biologics Research, Biotechnology Center of Excellence, Janssen R&D

Singapore has a clear focus in becoming the Asian hub for the life sciences arena with the highest number of regional headquarters setting up base here. Yet the influx of MNCs has not inspired a similar growth trend for local startups in the industry. What is it going to take to be a startup success story? Sulastri Kamis finds out from Clearbridge Accelerator’s Managing Partner Johnson Chen.

Introduction

Clearbridge Accelerator (CBA) was set up in 2010 as a Singapore technology incubator that aims to commercialize and translate core technologies from a laboratory into innovative products that result in sustainable and lasting enterprises. CBA provides the necessary funding, mentorship, operational and execution discipline to deliver determined and accelerated results. Our investment focus is on key emerging and high Intellectual Property (IP) disruptive technologies in the medical technology space.

The first genetically engineered therapeutic antibody, abciximab, was approved by the FDA in December 1994. Since then, more than 40 additional therapeutic antibodies (MAbs) or Fc fusion proteins (FcFPs) have been approved and are on the market. Another 50-plus MAbs and FcFPs are in Phase III clinical trials, of which approximately 75% are expected to be approved within the next five years; thus, by 2018, there should be at least 80 innovator MAbs and FcFPs approved for marketing worldwide (Table 1). With hundreds more currently in earlier stage clinical trials, this class of biologic therapy appears poised to take on a dominant role in the pharmaceutical industry, particularly as personalized medicine grows in importance.

MAbs, most of which are immunoglobulin G (IgG) molecules, take advantage of the extraordinary specificity with which they bind to targets such as pathogens, soluble proteins, and cellular receptors, neutralizing their activity or blocking their function. This specificity reduces off-target effects, and their low turnover rate in serum results in less frequent dosing as compared with smaller biologics and small molecule pharmaceuticals. In addition, their ability to engage cell surface targets not easily addressed by small molecules allows them to modulate the immune system or eliminate unwanted targets. Their large size, however, also limits their ability to penetrate cells or cross the blood brain barrier. Taken together, these characteristics make MAbs and FcFPs especially useful for targeting cancer cells and modulating the immune system. Indeed, of the 44 MAbs and FcFPs marketed in early 2013, 84% were indicated for treating cancer and immune-mediated conditions such as rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma, and transplant rejection (Table 1). In the coming years, non-cancer indications will become more prominent as therapeutic antibodies for conditions including hypercholesterolemia, osteoporosis, severe pain, and Alzheimer’s disease enter Phase III clinical trials [1].

Yet, even as excitement grows at the prospect of effectively treating some of the world’s most intractable diseases, financial concerns are squeezing innovation from both ends, with increasing research and development costs measured typically well over the $1billion range, as well as mounting concerns about who will pay the high price these treatments will inevitably demand. Most MAbs and FcFPs cost more than $10,000 per year, with the cost going as high as $100,000 per year for a few [2]. Payers are already beginning to limit what they are willing to reimburse for these treatments. For example, the United Kingdom, Canada, and Australia have all established agencies to consider both comparative effectiveness and cost effectiveness in determining which treatments will be covered [3]. An algorithm developed by the UK’s National Institute for Health and Clinical Excellence (NICE) takes into account a calculation of “quality adjusted life year” (QALY), essentially calculating the value of intervention [4]. For pharmaceutical companies, this heightened concern about cost effectiveness could impact decisions on whether to continue developing a drug if it is neither first-in-class nor likely to be best-in-class.

The Evolution of Monoclonal Antibodies

The development of today’s genetically engineered MAbs was made possible by seminal discoveries in the 1970s, including the first recombinant DNA experiments in 1973 by Boyer, Cohen and colleagues [5], followed by Köhler and Milstein’s development of techniques for generating hybridomas that secreted a single type of antibody (i.e., a monoclonal antibody) only two years later [6]. The first MAbs were mouse antibodies, but over the next three decades, “chimeric” and “humanized” antibodies that contained both mouse and human components, and then finally, fully-human antibodies were produced and developed into marketed drugs. Since they do not typically elicit a strong immune response, humanized and fully-human antibodies help to minimize some of the anti-drug immune responses associated with mouse or some chimeric antibodies.

FcFPs, generated by fusing the Fc portion of an immunoglobulin molecule with a protein or peptide, increase the serum half-life of the fused protein, thus prolonging its therapeutic activity. The Fc domain also enables the FcFPs to interact with different immune effector cells, if desired. The most commercially successful FcFP is etanercept, which was approved in 1998 for rheumatoid arthritis. Etanercept was generated by fusing the Fc domain of a human IgG1 to a portion of the extracellular domain of tumor necrosis factor (TNF). This construct competitively inhibits the binding of TNFs to cells, markedly reducing the production of the inflammatory cytokines and the subsequent pain and joint damage associated with rheumatoid arthritis. Etanercept also modulates other activities of TNF, so it is effective in psoriasis as well [7].

Antibody engineering has resulted in the ability to generate several alternative forms of MAbs that affect protein targets and modulate the immune system in a variety of different ways, and may provide alternative options for disease therapy.

  • Bispecific antibodies are antibodies that have the ability to engage two targets simultaneously [8]. Theoretically, for example, bispecific antibodies could bring together an immune effector cell such as a T cell with the targeted cell, such as a malignant B cell. Another strategy might be to target two signaling pathways that synergize to modulate a single disease. Although bispecific antibodies have yet to find their commercial niche, several companies are investing heavily into new technologies for making multi-specific antibodies, which may prove more powerful than existing approaches.

  • Antibody-drug conjugates (ADCs) join an antibody with a cytotoxic payload, combining the target specificity of antibodies with the therapeutic benefits of a highly cytotoxic drug, thus limiting the exposure of non-targeted cells and tissues to the drug. Early efforts to produce ADCs met with limited success due to instability, less-than-optimal cytotoxic drugs, and poor linker chemistries, but a new generation of more effective ADCs have emerged, two of which recently gained approval by the U.S. Food and Drug Administration (FDA). These include brentuximab vedotin to treat anaplastic large cell lymphoma (ALCL) and Hodgkin’s lymphoma and ado-trastuzumab emtansine to treat HER2-positive metastatic breast cancer [9].

  • Antibody fragments represent another alternative strategy for drug development, with three agents on the market, and several more in clinical trials. Most antibody fragments in development retain the portion of the antibody that confers target specificity but eliminate other portions (such as the Fc domain) that possess other functions. Because they are smaller in size, they may have better tissue penetrability and altered distribution patterns as compared with IgGs.

  • Alternative scaffolds, which are non-antibody proteins that bind targets similar to the way antibodies bind targets, offer another strategy for engineering molecules with multiple specificities [10]. This approach may be especially useful for complex, chronic diseases where multiple mechanisms converge, requiring multi-modal therapy.

New Targets — New Opportunities

Perhaps the biggest barrier limiting the development of new MAbs and FcFPs is the absence of new, well-qualified, and validated targets. Well-known targets have already been exploited, and while new targets are being found annually, it takes years to understand their biology well enough to consider them as bona fide therapeutic targets on which to develop new targeted therapeutics. While being first-in-class requires discovering and/or validating new targets, most large pharmaceutical companies have all but abandoned efforts at target discovery, leaving it to the purview of academia and small biotechnology companies, sectors that rely heavily on increasingly scarce federal and venture capital funding, respectively.

Despite the fact that MAbs represent the fastest growing segment of the pharmaceutical market, there are currently no U.S. or EU-approved MAbs or FcFPs targeting what is considered the most important class of drug targets, the G protein-coupled receptors (GPCRs) [11]. Mogamulizumab, which targets the GPCR, CCR4, was just recently approved in Japan for treatment of relapsed or refractory adult T cell leukemia (ATL). GPCRs regulate nearly all physiologic processes in the body and are broadly considered to be druggable. MAbs against GPCRs are in development at many pharmaceutical companies worldwide for a diverse group of diseases, including cancer, diabetes, inflammatory conditions, and infectious diseases. Ion channels have also long been recognized as important drug targets, particularly for diseases of the central nervous system (CNS), yet there are no MAbs in development that target ion channels.

Delivering MAbs to the brain and other inaccessible tissues remains one of the major challenges for the biologics field. Recent studies show that bispecific antibodies and other novel approaches, however, may enable antibodies to cross the blood brain barrier (BBB) in sufficient quantities to produce a treatment effect [12], giving significant hope that one day we will be able to address neurological disorders better with MAb and FcFP therapeutics. Efforts are also underway to construct submicron particles of monoclonal antibodies for delivery as inhaled agents to the lungs for the treatment of diseases such as asthma, lung cancer, and respiratory syncytial virus infection [13].

Looking to the Future

Will MAbs and FcFPs realize their true potential and continue to expand their influence in pharmaceutical development? A recent analysis of therapeutic MAbs and FcFPs (Table 2; from Ref [2]) summarizes the strengths, weaknesses, opportunities, and threats that will help answer this question. For new drugs to succeed in both the marketplace and the clinic, they must be truly innovative and efficient. Competition is stiff, driving companies to strive for first-in-class or best-in-class molecules. Since the successful companies in this market have all demonstrated capabilities that ensure optimization of potency, specificity, dosing frequency and route of administration, and safety, the challenge will be for these companies to generate differentiated molecules with unique properties. Drugs that provide incremental benefits will be increasingly difficult, if not impossible, to develop for commercial success given regulatory requirements and third-party-payor demands that drugs show not only statistical, but clinically meaningful, improvement over the standard of care. Yet recent history shows that even this high bar can be hurdled. Ustekinumab, a first-in-class MAb that targets the cytokines interleukins 12 and 23, was shown in pivotal trials not only to markedly improve the symptoms of psoriasis but improve quality of life [14]. Ustekinumab won regulatory approval in both the U.S. and Europe in 2009 and is covered by most insurers, who recognize that not only it is innovative and effective, having demonstrated superior efficacy to etanercept in the first ever head-to-head trial for a biologic in the category, but with psoriasis affecting over 100 million people worldwide, it addresses an important unmet medical need.

Just 15 years ago, the first MAbs and FcFPs were making their way onto the commercial market, and the entire industry watched and wondered if they were going to be a bust or boom. It is safe to say, 15 years later, that not only are therapeutic MAbs and FcFPs successful beyond what most people might have imagined in 1998, but that they will continue to be discovered and developed as great drugs targeting a wide variety of unmet medical needs. Our hope is that in another 15 years, hundreds of MAbs and FcFPs will be approved to help patients the world over in ways that we can only imagine today.

About the Author

Dr. William Strohl received his doctorate degree in microbiology and biochemistry from Louisiana State University. From 1980 to 1997, he rose from assistant to full professor in microbiology and biochemistry at the Ohio State University, where he focused on research in natural product biosynthesis. Dr. Strohl then joined Merck & Co. in 1997 where he led research in natural products microbiology, before focusing on antibody discovery. Most recently, he joined the Janssen Research & Development, LLC, organization to lead antibody drug discovery, and he currently serves as the Vice President of Biologics Research at the Biotechnology Center of Excellence within Janssen R&D. During his career, Dr. Strohl has more than 120 publications to his credit, secured several patents, edited two books, and recently published a book on therapeutic antibody engineering.

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