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The New Generation of Antibody Therapeutics: Current Status and Future Prospects

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ii The New Generation of Antibody Therapeutics: Current Status and Future Prospects

by K. John Morrow, Jr., PhD

Published in June 2012 by Cambridge Healthtech Institute

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iv The New Generation of Antibody Therapeutics: Current Status and Future Prospects

by K. John Morrow, Jr., PhD

About the Author K. John Morrow, Jr., PhD, is a writer and consultant for the biotechnology industry. He obtained his PhD in genetics from the University of Washington in Seattle, and completed his training with post-doctoral studies in Italy at the Universitá di Pavia and in Philadelphia at the Fox Chase Cancer Institute. He has held faculty positions at the University of Kansas and at Texas Tech University Health Sciences Center. His writings include over 200 peer-reviewed journal papers, non–peer-reviewed coverage of the biotechnology industry, books, and marketing reports. A number of companies, including Meridian Bioscience, Affitech, Henderson- Morley Biotechnology, Brandwidth Communications, and Emergent Technologies have taken advantage of his consultancy services, provided through Newport Biotechnology Consultants. He resides in Newport, KY.

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v Executive Summary The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Executive Summary

ntibody therapeutics remains the shining star of the may require dosing for years. For small-molecule drugs, costs run from pharma industry, yet there is a constant push to explore pennies to as much as a dollar per day, yet biopharmaceuticals average new approaches as pipelines become glutted with “me-too” $22 per day. The top 6 biologic drugs take up 43% of the Medicare Part A products. Currently approved antibodies are expecting a B drug budget. And the situation can only get worse. The world’s 9 most growth from 22 billion euros ($32 billion) in 2008 to approximately 40 expensive drugs all run in the range $200,000 to $400,000 per annum, billion euros ($58 billion) by 2014. and with proper therapy, individuals with these conditions may enjoy Despite increasing R&D budgets, Big Pharma has been unable to decades of life. increase its yield of approved drugs per dollar of R&D expenditures. This Antibodies are a formidable and elegant technology, yet costly, report profiles many approaches underway to increase an abysmal record representing complex molecules that can bind to a wide range of of productivity. While these strategies may take effect in the long run, molecular sites. Thirty-one antibodies have been approved by the FDA they are unlikely to have immediate repercussions. for treatment of a range of disorders, including cancer and autoimmune Today’s biotech industry is fiercely competitive and can be a “winner dysfunction (and one for infectious disease). Whereas antibodies have takes all” environment. As the battle heats up, the climate encourages been demonstrated to extend length and quality of life in a number companies to overpromise. There are many new technologies that are of cases, they do not constitute a cure and they cannot be used alone, hyped as delivering new treatments in the next 5 years. These rosy but must be combined with conventional . They are predictions represent a disconnect with reality, as they don’t take into complicated to administer and extremely expensive. account the years and uncertainty of clinical trials that these compounds The difficulties encountered with potential therapeutic antibodies must go through. for Alzheimer’s disease are illustrative of the plight of the industry as The success of biologics, especially antibodies, has been accompanied a whole, and may explain why the introduction of new antibodies has by increasing concerns over their cost, and whether it is sustainable proceeded at such a sluggish pace. Despite the amazing progress in our in the long run. Not only do antibodies have a high unit cost, but they understanding of biological systems in the last 60 years, we still lack a are frequently employed in the treatment of chronic conditions and complete and thoroughgoing knowledge of the molecular nature and the

vi Executive Summary The New Generation of Antibody Therapeutics: Current Status and Future Prospects

interrelationship between the components that drive complex disease processes. In the case of Alzheimer’s disease, there is as yet no agreement on whether the accumulation of the beta amyloid protein is a cause or an effect of the disease, or of the role of neurofibrillary plaques and tangles. At the same time, antibodies may carry the baggage of unknown and misunderstood side effects. The combined effect of these gaps in our knowledge can mean that antibodies will not ameliorate their target disease, while at the same time their administration may be accompanied by serious and unanticipated side effects. Predictions for the future of cutting-edge antibody technologies are that robust growth will continue despite many roadblocks and uncertainties in the overall picture of drug development. The market will continue to be dominated by whole antibody molecules, mainly IgGs. It is anticipated that bispecific antibodies and antibody drug conjugates will be a growing component of the overall market. Five to ten years from now, many of the challenges of alternative scaffolds will be resolved and therapeutic products based on these platforms will appear in significant numbers. A decade from now, systems biology will be a powerful driving force within the industry, and will generate models of biological networks that will enable predictive development of entirely unique and innovative drugs.

vii Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Table of Contents

Executive Summary vi

Chapter 1 Introduction, Scope, and Objectives 1 1.1. Introduction 1 A Long History of Biotherapeutics 1 The Rise of Antibodies 2 The FDA Approval Process 6 Is the FDA Moving Too Slowly? 7 Cost Factors in Antibody Therapeutics 7 1.2. Current Products 9 Avastin () 9 Cimzia (certolizumab pegol) 11 SIMPONI (golimumab) 11 ILARIS (canakinumab) 12 STELARA (ustekinumab) 12 ARZERRA () 12 Prolia (denosumab) 13 Actemra (tocilizumab) 13 Benlysta (belimumab) 14 YERVOY () 14 ADCETRIS (brentuximab) 14 1.3. Business Environment and Market Forces 15 World Economic Outlook 15 Economic Outlook for Antibody Technologies 16 Drug Development Costs 19

viii Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

1.4. Opportunities for Future Products 20 Antibodies in Development 20 Phase III Antibody Studies 22 22 22 AMG 386 23 Itolizumab 23 Factor VIII-Fc and Factor XI-Fc 23 CINQUIL (reslizumab) 24 24 Bosatria (mepolizumab) 24 25 25 Epratuzumab 25 Tabalumab 25 Solanezumab 26 26 Secukinumab 26 Vedolizumab 26 Bapineuzumab 26 Inotuzumab (CMC-544) 26 Sarilumab 26 Zanolimumab (HuMax-CD4) 27 27 Otelixizumab 27 Other Antibodies in Earlier Stages of Development 27 IL-1–Blocking Therapies 27 Adimab Antibodies: MM-151 29 30

ix Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Alzheimer’s Disease: Therapeutic Antibodies 30 A Delivery Strategy That Overcomes the Blood-Brain Barrier 31 A New Trial Will Follow Progression from the Preclinical State to Expression of the Full-Blown Disease 32 New Antibody Selection Technologies 32 Novartis and AnaptysBio 32 Ylanthia (MorphoSys) 32 Small Engineered Bispecific Antibodies 34 Improving Efficacy and Druggability of mAbs 35 A New Yeast Display Technology 35 1.5. Summary, Objectives, and Outlook 35

Chapter 2 Antibody Conjugates and Other Payloads 37 2.1. Past and Present 37 2.2. General Methodology of Construction 42 2.3. Notable Antibody-Toxin Conjugates 43 AGS-16M8F 43 AGS-5ME 43 -Auristatin E 43 Ontak/DT 44 -Emtansine 44 Lorvotuzumab- (IMGN901) 45 Cintredekin Besudotox 45 MR1-1–PE 45 MEDI547-mcMMAF 45 CAT-8015–PE 46 BL22-PE 46 LMB-2–PE 46 SS1P-PE 46 Inotuzumab-Ozogamicin 46

x Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

PSMA ADC/PSMA ADC-Auristatin E 47 SAR-3419 47 Brentuximab-Vedotin 48 2SGN-75–Auristatin F 48 HuM195/rGel-rGelonin 48 RFT-5–dgA 48 (CAT-8015–PE38) 48 CDX-011 49 2.4. Clinical Trials 49 HuM-195/rGel: A Unique Immunoconjugate 49 2.5. Commercial Development 50 Aldevron (Formerly GENOVAC) 50 GenScript 50 Maine Biotechnology Services 50 Ambrx 50 Seattle Genetics 51 Genentech 51 Philogen 52 2.6. Summary and Future Directions for Antibody-Drug Conjugates 52

Chapter 3 Multispecific and Multifunctional Antibodies 53 3.1. Challenges and Opportunities 54 3.2. The Rundown on Bispecific Antibody Companies 56 Ablynx 56 Affimed 56 Fresenius 56 MacroGenics 56 Merrimack 57 Micromet 57

xi Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Pfizer 58 Sanofi 58 Trion 59 Zyngenia 59 3.3. Methods of Construction 59 3.4. Recombinant Polyclonal Antibodies 60 3.5. Anti-Angiogenic Antibodies: Boom or Bust 62 3.6. Challenges and Opportunities in Immunocytokines 64 Provenance 64 3.7. Cutting-Edge Concepts in Bispecific Antibody Development 64 DuoBody Technology 64 Chemically Programmed Antibodies: CovX 65 3.8. Summary and Conclusions 65

Chapter 4 Biosimilars and Biobetters: Opportunities and Challenges 67 4.1. Biosimilars: Challenges and Opportunities 67 An Uncertain Period 67 A Rundown on Biosimilars 68 Will Biosimilar Cost Savings Materialize? 70 4.2. Commercial Development and Marketplace 71 4.3. Role of the EMA and FDA in Approval and Regulation of Biosimilars 71 EU Initiative 71 Canadian Biologics Regulatory Guidelines 74 US Regulation and the Affordable Healthcare Act 74 4.4. Biobetters: Unique Products or Improved Biosimilars? 75

xii Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Chapter 5 Advances in Product Development Technologies 77 5.1. Overview 77 5.2. Biomanufacturing Challenges 77 5.3. Overview of Bioprocessing Technology 79 Escherichia coli 79 Other Bacterial Hosts 80 Yeast 81 Saccharomyces cerevisiae 81 Pichia pastoris 82 Insect Cells 82 Dictyostelium discoideum 83 5.4. Downstream Processing: Improvements in Product Purification 83 5.5. New Emerging Technologies 84 More and Better Disposables 84 Dealing with Inclusion Bodies 84 Modifying Proteins to Improve Their Stability 84 New Wrinkles in Bioprocessing 85 Wanted: Very Rapid Micropurification Strategies 85 Non-Natural Amino Acids 86 Improvements in Product Purification from Plant Material 86 5.6. Failed Technologies and Lessons Learned 87 Failed Therapeutics 87 Inclusion Bodies 87 Host Cell Proteases, Endotoxins, and Pyrogens 87

Chapter 6 IP Challenges, Deal Structures, Mergers and Acquisitions, and Future Opportunities 89 6.1. IP Thicket for Biosimilars 89 6.2. Collaboration and Partnering 90

xiii Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Symphogen 90 Activartis Biotech 90 MorphoSys 91 ImmunGene 91 BioInvent 91 Eli Lilly 91 Apexigen and Gansu Duyiwei Biological Pharmaceutical 92 GlaxoSmithKline-Tolerx Collaboration 92 6.3. Mergers and Acquisitions 93 Bristol-Myers Squibb Completes Acquisition of Inhibitex 95 Sanofi Signs Rare Disease Pact with CRG 95 Illumina Rejects Roche Tender Offer 95

Chapter 7 Marketed and Pipeline Products 96 7.1. Marketed Products: Current Status and Future Forecast 96 7.2. Clinical Development: Lessons Learned From Successes and Failures 96 7.3. The Centocor Experience with Centoxin 97

Chapter 8 Profiles of Selected New-Generation Antibody Companies 100 8.1. Overview 100 MacroGenics 100 Micromet 101 Bicycle Therapeutics 101 8.2. Business Strategy 101 8.3. Technology and Product Pipeline 101 Zyngenia 101 Philogen 102 T2 Biosystems 103

xiv Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Molecular Partners 104 Tolerx 104 Crescendo Biologics 105 Haptogen 105 Trion, MacroGenics, and Micromet 105

Chapter 9 Strategic Issues 106 9.1. Outlook for the Future 106 Why Do Antibodies Fail? 106 Naked or Nattily Dressed: Which Is Best? 107 Escape from the Valley of Death 108 Next Five Years 109 Alternative Affinity Tools 109 Technologies, 10 Years Plus 110 Intracellular Immunity 111 Demands, Needs, Directions 111 New Target Search 112 Cost Containment 113 We Need to Quit Overpromising 113 Systems Biology Is Not the Holy Grail 114 There Are No Surprises 114 9.2. Systems Biology and Design of Innovative Therapies 114 Future of the Proteome 115 Building More Antibodies 115 Systems Biology Companies 116 9.3. Immunotherapeutics and Vaccines 118 9.4. Impact of Nanotechnology in Antibody Therapeutics Development 121 Magnetic Nanoparticles 122 Antibody-Conjugated Nanoparticles 123

xv Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Nanodelivery Systems for Antibodies 123 Nanotechnology and Regulatory Concerns 124

References 125 Appendix 140 Company Index 142 About Cambridge Healthtech Institute 151

Tables Table 1.1. FDA-Approved Recombinant Antibodies 2 Table 1.2. Costs of the Most Expensive Drugs 8 Table 1.3. Various Estimates of Pharma Sales 18 Table 1.4. Phase III Antibody Trials 20 Table 1.5. IL-1–Blocking Therapies Marketed or In Development for the Treatment of Autoimmune Disorders 28 Table 1.6. Many Antibodies Are Directed Against the Same Target 29 Table 2.1. Immunotoxins: Current Status of Clinical Trials 40 Table 3.1. Bispecific Antibodies in Clinical Trials 55 Table 4.1. EMA-Approved Biosimilars 72 Table 5.1. Non-Microbial Protein Production Platforms 78 Table 5.2. Important Approved Therapeutic Protein-Based Products From E. coli 79 Table 6.1. Notable Antibody Collaborations 93 Table 9.1. Properties of Affinity Molecules 110 Table 9.2. Systems Biology Companies 117 Table 9.3. Antibodies Against Infectious Disease Agents in Current Trials 120

Figures Figure 1.1. A Slow Rate of Approval for Antibodies 5 Figure 1.2. Structure of the Akt Molecule 10 Figure 1.3. Anti-TNF Agents Infliximab, Adalimumab, and Certolizumab Pegol 11 Figure 1.4. Zoledronic Acid 13

xvi Table of Contents The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Figure 1.5. Global GDP Growth 15 Figure 1.6. CD38 Molecule 30 Figure 1.7. Structure of the Three-Helical Albumin-Binding Domain (ABD) from Streptococcal Protein G (PDB: 1GJT) 34 Figure 2.1. Chemical Structures of mAb-Drug Conjugates 38 Figure 2.2. An Antibody-Drug Conjugate 42 Figure 2.3. Denileukin Diftitox (Ontak) 44 Figure 2.4. Recombinant Immunotoxin BL22 and LMB-2 46 Figure 2.5. How the PSMA ADC Works 47 Figure 3.1. A Conventional Antibody and Its Derived Fragments 54 Figure 3.2. The Scaffold Antibody and the Bispecific CVX-241 Antibody 58 Figure 3.3. Symphogen’s Sym004 mAb Mixture Enables Novel Mechanism of Action 61 Figure 3.4. Peregrine Clinical Trials in Progress 64 Figure 8.1. A 4-Repeat DARPin Molecule 104 Figure 9.1. Structure of the Armadillo Repeat Region of Beta-Catenin 112 Figure 9.2. Honeycombed Particles Filled with Cancer Drugs Act like Time-Release Capsules at Tumor Site 124

xvii Introduction, Scope, and Objectives The New Generation of Antibody Therapeutics: Current Status and Future Prospects

But the picture is complex. There are a number of studies in the Blank et al. (2011),18 who find “Despite substantial costs of predictive literature that assess the cost effectiveness of anticancer antibodies, testing, it is economically favorable to identify patients with KRAS and and in numerous cases there is significant benefit at manageable cost. BRAF mutations.” For instance, Macedo et al. (2010)77 studied the cost-effectiveness of So at this juncture, we have a formidable and elegant, yet costly Herceptin in treating Her-2+ breast cancer patients in Portugal during technology that can produce conveniently and on demand complex a 5-year period. They calculated incremental cost effectiveness ratio per molecules that can bind to a wide range of molecular sites. Thirty-one year of life gain, as well as quality-adjusted life years gained. The results antibodies have been approved by the FDA for treatment of a range of demonstrate that patients experienced improved survival and cost disorders, including cancer and autoimmune dysfunction. Whereas effectiveness of the therapy. antibodies have been demonstrated to extend length and quality of life in Other reports are similar to that of Meads et al. (2010),86 who a number of cases, they do not constitute a cure and they cannot be used document that 8 months of treatment with for metastatic alone, but must be combined with conventional chemotherapy. They are colon cancer cost ca. £23,000 for an average man and £18,000 for complicated to administer and extremely expensive. Thus they hardly an average woman. The authors suggest, rather cryptically, that it is represent the “magic bullet” proposed by Paul Ehrlich 100 years ago. uncertain whether this constitutes good value for the money. In any case, survival benefits of antibody adjuvant therapy are measured in months. 1.2. Current Products When antibody costs are compared with driver side airbags ($70,000 per quality year of life saved [www.riskworld.com/news/97q1/nw7aa028. In this section, we will review the current antibodies that were htm]), antibodies—as expensive as they are—look like a bargain. A recently approved or are under evaluation and close to approval. There course of treatment runs in the range of $50,000, so we must conclude are 11 antibodies on the market that moved through this process in that at this stage antibody therapeutics is a work in progress. Further 2008 and subsequent years. Here, we evaluate them and assess follow- in this report we will discuss the development of new small and large up investigations, completed in the years following their approval. molecules, as well as a thorough evaluation of different combinations This approach will provide us with an assessment of the state of the and treatment regimes. art, and allow us to evaluate the needs and direction of antibody An interesting hypothetical argument has been put forward (Eng technology today. 2010)45 regarding the use of cetuximab for colon cancer. The author posits that testing patients for the KRAS status of their tumors would Avastin (bevacizumab) be expensive, but would be extremely cost effective, as it would allow Avastin, a humanized mAb, inhibits vascular endothelial growth factor elimination of non-responder patients. It is clear that the search for A (VEGF-A). It has been approved for the treatment of metastatic appropriate biomarkers will be required if we are to advance the cause colon and rectal cancer and in combination with chemotherapy for of personalized medicine. Similar conclusions have been arrived at by the treatment of lung cancer. It is under evaluation for the treatment

Search 9 Antibody Conjugates and Other Payloads The New Generation of Antibody Therapeutics: Current Status and Future Prospects

collaboration between ImmunoGen and Genentech. It is currently being Cintredekin Besudotox evaluated for the treatment of metastatic breast cancer. A recombinant chimeric protein with antitumor activity, composed The parent company, Roche, will apply for marketing approval for first- of interleukin 13 (IL-13), which binds to the IL-13 receptor, expressed line use in 2014 using MARIANNE data and recently noted its intention on certain tumor cells. The IL-13 molecule is linked to a mutated form of applying for approval of trastuzumab-emtansine used alone and in of Pseudomonas exotoxin A. The mechanism of action of cell killing is combination with for this use. caspase-mediated apoptosis of tumor cells via a mechanism involving mitochondrial damage; it also catalyzes the transfer of ADP ribose from Lorvotuzumab-Mertansine (IMGN901) nicotinamide adenine dinucleotide (NAD) to elongation factor 2 in Described as a CD56-targeting TAP compound, this drug is touted as eukaryotic cells, thereby inactivating elongation factor 2 and inhibiting a potential therapy for the treatment of small-cell lung cancer (SCLC) protein synthesis. There are no reports in the literature of current and other cancers that express CD56. TAP is ImmunoGen’s acronym clinical trials. for their portfolio of cancer-cell toxins that can be attached to mAbs for targeted delivery to cancer cells. According to the company website, TAP MR1-1–PE technology also includes a group of engineered linkers, which may be Convection-enhanced delivery is a novel method of drug attached to the antibody while it is in the bloodstream and then allow its administration that allows direct parenchymal infusion of therapeutics, controlled release and activation once internalized inside the cancer cell. bypassing the blood-brain barrier. It involves the use of strategically The Phase I trial establishes the dose of IMGN901 given with standard placed intracranial catheters that deliver drugs directly into the tumor care for SCLC, etoposide plus carboplatin (E/C), to be used in the bed, in a process termed CED (Bobo et al. 1994).20 This agent is an Phase II component. The Phase II part assesses IMGN901 plus E/C affinity-matured scFv specific for EGFRvIII, MR1-1 fused to PE. MR1- compared to E/C alone in patients with newly diagnosed SCLC. The 1–PE is currently in Phase I trials. goal of this trial is to assess whether adding IMGN901 to E/C therapy meaningfully changes the duration of progression-free survival for SCLC MEDI547-mcMMAF patients. The Phase II portion of the study is anticipated to begin by This antibody-drug conjugate was evaluated in a Phase I trial. The mid-2012. molecule consists of a human antibody directed against the EphA2 IMGN901 is currently being assessed for the treatment of multiple antigen linked to auristatin. EphA2 is a member of the Eph family myeloma in combination with lenalidomide plus dexamethasone, a of receptor tyrosine kinases. However, the drug treatment was standard of care for this cancer. accompanied by severe side effects and efforts to engage in additional trials were subsequently discontinued.

Search 45 Multispecific and Multifunctional Antibodies The New Generation of Antibody Therapeutics: Current Status and Future Prospects

3.2. The Rundown on Bispecific Antibody Companies antigen on the tumor target cells and CD16A on NK cells as immune effector cells. Successful preclinical performance encouraged the entry Ablynx of the drug into Phase I trials, which indicate a specific and very effective The aim of this company’s investigations is to develop a new protein- engagement of NK cells, inducing fast and strong ADCC in combination based TNF therapeutic, using novel protein moieties with high with good safety and tolerability. potential efficacy, optimizing the product for ease of delivery. Ablynx is collaborating with Pfizer in the development and evaluation of the Fresenius nanobody, ozoralizumab (ATN-103). Nanobodies are therapeutic Fresenius Biotech is focused on delivering therapeutics designed proteins that contain the structural and functional properties of naturally for patients with serious illnesses characterized by a high degree of occurring heavy-chain antibodies derived from camelids. This novel unmet need. The company develops immunotherapeutic products tumor necrosis factor inhibitor is classified as a humanized, trivalent, based on a range of antibody technologies. Its lead product is Removab, bispecific molecule containing 2 human TNF‑binding domains linked to which contains the . Its targeted a human serum albumin-binding domain. mechanism of action destroys cells from EpCAM-positive carcinomas. Pharmacokinetic-pharmacodynamic modeling of data from a Phase I/ It simultaneously recruits immune cells, and activates them to destroy II study in rheumatoid arthritis patients was performed to understand the cancer cells. Removab was developed in cooperation with TRION the relationship of ATN-103 exposure to clinical performance. Pharma. Fresenius Biotech holds the EU Marketing Authorization and TNF is expressed as a trimeric transmembrane protein that can be worldwide marketing rights for Removab. proteolytically cleaved by TNF-converting enzyme to release its soluble form. Both forms of TNF interact with the TNF receptors TNFR 1 MacroGenics and TNFR 2. Inhibition of TNF has been shown to be an effective Bispecifics and related technologies have generated substantial treatment of rheumatoid arthritis. They have a high degree of sequence enthusiasm with major pharma companies. MacroGenics and f-star and structural homology to human immunoglobulin variant heavy have both signed agreements with Boehringer to develop innovative chain domains. antibody compounds. In November 2011 Ablynx regained the worldwide rights from Pfizer MacroGenics has developed the Dual-AffinityR e-Targeting (DART) to develop and commercialize anti-TNF alpha nanobodies. platform technology, which is focused on dual specificity “antibody-like” therapeutic proteins capable of targeting multiple different epitopes Affimed with a single recombinant molecule. The platform employs a proprietary This firm is evaluating a bispecific, tetravalent human antibody covalent linkage to produce molecules having superior stability, optimal referred to as TandAb antibody, or AFM13, to treat Hodgkin lymphoma. heavy and light chain pairing and predictable antigen recognition. The AFM13 is a RECRUIT-TandAb, simultaneously targets the CD30 company’s antibody library includes 1,500 purified antibodies directed

Search 56 Biosimilars and Biobetters: Opportunities and Challenges The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Hospira said US biosimilars are likely to sell at discounts of 20–40% stated that they intend to commercialize biosimilars by 2016, and then from the branded competitors. There is another roadblock to cost expand into innovative biologics from there. The joint venture, which effectiveness: A company seeking to make a generic version of a will develop, manufacture, and market biosimilars, will be based in Seoul medicine will need to share its application with the brand-name and contract with Biogen Idec and Samsung Biologics for technical manufacturer, a potential source of strife or lawsuits, over how the development and manufacturing services. generic was made. Samsung will contribute $255 million for an 85% stake, and US patent expirations for biotech drugs will occur in 2013 for Biogen Idec will be the minority partner, putting up $45 million to EPOGEN and another Amgen drug, Neupogen. The FDA said in early cover the remaining 15% of the initial costs of the venture. Samsung February it had held discussions for a total of 35 potential biosimilar will contribute the biomanufacturing plant, while Biogen Idec products, but had yet to receive an application. will contribute its expertise in protein engineering and biologics Hospira puts the cost of getting a biosimilar drug approved for the US manufacturing. The joint venture has agreed upon an initial portfolio, market at $100 million to $200 million per product, compared with drug but has yet to reveal its details. industry estimates of about $1 billion for new brand-name medicines. However, some estimates (see Chapter 1) put the cost at a much higher 4.3. Role of the EMA and FDA in Approval and Regulation of figure. If these large numbers are correct, then the biosimilar market Biosimilars becomes much more appealing. EU Initiative 4.2. Commercial Development and Marketplace The European and Canadian regulatory agencies have already passed legislation to deal with approval of biosimilars, and the The growth of the biosimilars market is driving a large-scale migration issue has finally been resolved in the United States, although not to of companies that would not ordinarily be so motivated into this area everyone’s satisfaction. (Swinderman 2012).122 Samsung, the Korean company better known The European legislation is framed around the concept that for its electronics products, recently announced that its biologics bioequivalence is not sufficient for approval but rather additional studies division was aiming to become a key player in drug development of will be required. Thus, when the current statutes were agreed upon, biosimilars. The company has initiated a joint venture with Biogen Idec, substantial nonclinical and clinical data were made mandatory. The which focuses mainly on neurodegenerative diseases, hemophilia, and European Medicines Agency (EMEA) handles marketing authorization autoimmune disorders. applications through the Committee for Medicinal Products for Human Samsung will construct a biopharmaceutical manufacturing plant in Use. Clinical trials are carried out at this time and the EMEA monitors the Incheon Free Economic Zone in Songdo, Incheon, South Korea. their safety and performance after they have entered the market. The Representatives of the newly formed division, Samsung Biologics, have period of data exclusivity or patent protection (in which other firms are

Search 71 Advances in Product Development Technologies The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Chapter 5 Advances in Product Development Technologies

5.1. Overview According to Langer (2012),69 there is a trend toward the adoption of innovative expression systems and other manufacturing platforms by the Development of antibody products starts with the R&D necessary to biosimilar/biobetter/biogeneric industry, moving away from 20 year- build a promising candidate, but subsequently bioprocessing expertise old technology. Although biosimilar manufacturers will have technical will be required to produce sufficient quantities of the drug through advantages with newer technology, established companies that are GMP manufacturing standards. After a successful Phase I trial on a small developing the new drugs will have long paid off manufacturing facilities. scale, much larger quantities will have to be produced for large-scale This will mean that companies will adopt aggressive business models in trials. If these are successful and if an FDA approval results, then much order to be competitive. Today such companies are widespread, present larger volumes will be required to fulfill the needs of the marketplace. in virtually every biotechnology-capable region. Of the nearly 400 The production demands for antibody fragments, conjugates, and organizations involved in biosimilars/biobetters development, more bispecifics may be quite different and challenging. than 30 companies are based in India and 14 in China. Bioprocessing is a rapidly changing field, responding to the demands of the industry. There are a number of companies active in generating 5.2. Biomanufacturing Challenges products for both upstream and downstream processing. Here we discuss some recent developments in bioprocessing relevant to the The bioprocessing industry is today skewed toward the use of needs of the antibody sector. For more details, the reader is referred mammalian cells at the upstream end and Protein A for monoclonal to the Insight Pharma Report, Therapeutic Protein Production: A antibodies and Fc chimeras at the downstream of the equation. This Changing Landscape (www.insightpharmareports.com/reports_report. is the result of the early adoption and approval of pharma products aspx?id=100151&r=7309). produced in mammalian cells and the fact that most of the early biopharmaceuticals were antibodies, which are notoriously difficult

Search 77 IP Challenges, Deal Structures, Mergers and Acquisitions, and Future Opportunities The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Chapter 6 IP Challenges, Deal Structures, Mergers and Acquisitions, and Future Opportunities

6.1. IP Thicket for Biosimilars are now under scrutiny by biotech and pharmaceutical companies, as these rulings may have a profound effect on both prices and profits for Patent thickets are broadly defined in academic discourse as “a manufacturers (see Chapter 4). dense web of overlapping intellectual property rights that a company The concerns are over the question of what to patent and what to must hack its way through in order to actually commercialize new keep as a trade secret, according to attorneys who were interviewed for technology” (Shapiro 2000).115 Such patent thickets, as a result of the piece. This has placed the long-established practice of sequestering multiple blocking patents, naturally discourage and stifle innovation (op of trade secrets in the spotlight. Because the manufacturing processes cit. 2000).115 Claims in such patent thickets have been characterized as require disclosure of all relevant information, manufacturers may not “often broad, overlapping, and conflicting— a scenario ripe for massive wish to make details available which other firms could circumvent patent litigation battles in the future” (Anonymous 2004).5 Therefore, through minor manipulations of the protocols. However, protecting business planners, patent lawyers and patent agents should steer their trade secrets is thought to be more dicey than pursuing patents, since clients away from such potential black holes. They may also need to there is a strong incentive for companies to entertain ideas that push or analyze the patent landscape to gauge the “white space” opportunities even exceed the strictures of legality in order to gain access to valuable (no overlapping patents) prior to R&D efforts, patent filing, or information. To protect trade secrets, companies may have to go to commercialization activities. elaborate protective schemes. The FDA has issued guidelines for development of biosimilars (Valigra There is a widespread belief that biosimilars will cost less than a new, 2012; www.masshightech.com/stories/2012/02/13/daily28-FDA- innovative drug, since the development costs will be much less. However biosimilars-guidance-sparks-reviews-of-IP-protection.html), which this point of view is not universally accepted.

Search 89 Strategic Issues The New Generation of Antibody Therapeutics: Current Status and Future Prospects

slim. Second, failure to generate antibodies against all possible a therapy into Phase III on the basis of shaky data from earlier-stage epitopes of a target may lead to highly promising disease targets trials. In some cases, data from Phase II trials is only on the borderline being overlooked. Lack of diversity in antibody generation of statistical significance. If the mathematical statistical analysis is not means that putative targets often are not fully ‘interrogated’ with performed by well-qualified experts, there are many places in the course antibodies intended to probe their role in disease processes. The of the study where errors can occur. Of course, the most blatant is Ylanthia technology was specifically conceived and designed to the analysis of only those trials which generate a positive result. Since overcome these limitations.” 5% is the accepted cutoff level, eliminating trials from consideration There are a number of companies covered in this report that that do not generate a positive result can bias the analysis. Moving a provide excellent contractual services for the production of drug forward on this basis can have unfortunate consequences (often antibodies with good binding properties and high specificity. measured in the millions of dollars of loss). Of course, the problem is that this is only a part of why antibodies fail. Naked or Nattily Dressed: Which Is Best? 2. Mid-project failure. If antibodies fail early on, then this saves We have noted previously that the great success in antibody drug the money and inconvenience of going into clinical trials. development up to this time has come almost exclusively through whole However, many antibodies prove unsatisfactory in early clinical immunoglobulin molecules, unconjugated and unmodified, so-called trials, because they have serious side effects that were not “naked” antibodies. While a new generation of antibody therapeutics revealed in preclinical studies. is under intensive investigation at this time, most of the contributors 3. Late-stage failure. This is the worst, the horrific, greatly interviewed in the course of this report feel that naked whole antibodies feared train wreck. For example, GlaxoSmithKline and Tolerx will be a significant, if not the most important, immunotherapeutic announced (March 12, 2012) that the Phase III DEFEND-1 for the next few years. As our understanding of the mode of action study of otelixizumab, an investigational humanized anti- of antibodies has been investigated, an explanation for their potency CD3 , did not meet the primary efficacy becomes clear. endpoint of change in C-peptide at month 12 in patients with It has been well-known since the early days of recombinant antibody new-onset autoimmune type 1 diabetes. While the company therapy that receptor blockage, cytostasis, apoptosis, complement- puts forth an air of optimism, it appears that this makes future dependent cytotoxicity, and antibody-dependent cytotoxicity all development of the product unlikely. GlaxoSmithKline states contribute to the demise of the tumor cells following injection of that it will continue to explore options for future trials of antibodies such as Rituxan (). But this is not the only the drug. mechanism by which antibody therapy can successfully fight various So antibodies fail for the same reasons other drugs fail—because cancers. Abès et al. (2010)1 and Abès and Teillaud (2011)2 have the basic science is not well-understood, and project directors move commented on the ability of therapeutic antibodies to allow the host

Search 107 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Company Index

A Abbott 3, 6, 20, 22, 52 Ablynx 29, 55-56, 105 Activartis 90-91, 93 Active Biotech Research 20 Adimab 29 Affimed 55-56 Agensys 43 Alcon 112 Aldevron 50 Alexion 4, 8 Allergan 113 Alopexx 121 Ambrx 50-51 Amgen 4, 19-20, 23, 28, 70-71, 109 AnaptysBio 32 Apexigen 92-93 Astellas 40 AstraZeneca 17, 19, 117, 120 Avanir 120 Aventis 41, 117, 121 Avid Bioservices 63, 113

Search 142 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

B Banner Health 32 Bayer 16, 40, 52 Bayer-Schering 40 BG Medicine 117 Bicycle Therapeutics 101 Biocon 20, 23 Biogen Idec 3, 20-21, 23, 29, 40, 71, 87, 90, 95, 109 BioInvent 91, 93 BioMarin 8 Biopartners 74 BioSeek 117 Biosynexus 120 Biotest 40 Boehringer Ingelheim 7, 17, 100 Boston University School of Medicine 117 Bristol-Myers Squibb 5, 17, 20, 22, 25, 40, 95, 117, 120

C Celldex 40 Centocor 40, 97-98 Centre for Genomic Regulation 95 Cephalon 20, 24, 29 Ception Therapeutics 24 Chugai 4 CIMAB 20 City of Hope 1 Corixa 3 CovX 58, 65 Crescendo Biologics 105

Search 143 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Crucell 120 CT Arzneimittel 72 CureTech 120 Cytos 28

D Domantis 29 Dow Chemical 118

E Eisai 26, 40 Elan 117 Elusys 120 Emergent BioSolutions 120 Entelos 116-117 ESBATech 29, 112 ETH 64

F Fraunhofer Institute 86 Fresenius 29, 55-56 f-star 56, 100

G Gansu Duyiwei Biological Pharmaceutical 92-93 GE 94 Gene Network Sciences 116, 118 Gene Networks International 118 Genentech 1-4, 6, 21, 24, 31-32, 40, 45, 51, 55 Genmab 4, 17, 22, 27, 29-30, 64-65, 87

Search 144 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Genomatica 118 GenScript 50 Genstruct 116, 118 Genzyme 3, 8 GlaxoSmithKline 3, 16, 21, 24, 92-93, 107, 117 Glycart 21, 29 GlycoFi 82 Goodwin Biotechnology 67, 109

H Haptogen 105 Hexal 72 Hospira 70-71, 73 Human Genome Science 4 Human Protein Atlas 116

I Illumina 95 ImClone 3, 21, 25 ImmunGene 91, 93 Immunocore 55 ImmunoGen 17, 40, 44-45, 47, 51-52, 96 Immunomedics 21, 29, 55 Indiana University School of Medicine 91 Inhibitex 95 Insmed 109 Institute for Systems Biology 114 Institute of Neuroscience 92 INSYS 40 Ivax 40

Search 145 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

J Janssen 22 Johnson & Johnson 2-4, 31, 93, 117, 120

K KaloBios 121 Kenta Biotech 120 Kowa 28

L LFB Biotechnologies 121 LigoCyte 83 Lilly 1, 3, 21, 25, 28-31, 91-93 Lonza 109 Los Alamos National Laboratory 115

M MacroGenics 17, 55-57, 59, 100, 105, 120 Maine Biotechnology Services 50 Mass Biologics 121 M.D. Anderson Cancer Center 48 Medarex 11, 40, 120 Medice Arzneimittel Pütter GmbH & Co. KG 72 MedImmune 2, 41-42, 48, 57, 120 Medivation 31 MENTRIK 29 Merck 17-18, 82, 94, 105, 109, 121 Merck Serono 18, 105 Meridian Life Science 83 Merrimack 29, 35, 55, 57

Search 146 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

METabolic EXplorer 118 Micromet 55, 57, 101, 105 Millennium 21 Molecular Partners 104 Momenta 90 MorphoSys 17-18, 32-33, 91, 93, 106 Morphotek 21, 26

N National Cancer Institute (NCI) 7, 37 NIH 32, 81, 116 Novartis 2, 4, 17, 21, 28-29, 31-33, 41, 117

O Ohio State University 80 Optimata 118 OSI 65

P Pall Life Sciences 83 PDL 121 Peregrine 63-64, 121 Pfizer 3, 16-17, 22, 29, 31, 41, 51-52, 55-56, 58, 65, 101, 105, 109, 117 Pharma-Planta 86 Philogen 52, 64, 102-103 Predictive Physiology & Medicine 117 ProFoldin 84 Progen 29 Progenics 41, 47, 121 Provenance 64

Search 147 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Q Quintiles 90

R Ratiopharm 72-73 Regeneron 8, 22, 26, 28 Roche 2-4, 6, 13, 17, 24, 27, 29, 31-32, 40, 45, 51-52, 63, 87, 95

S Samsung 71, 109 Sandoz 72-74 Sanofi 17, 26-27, 41, 47, 55, 58, 95, 121 Sanofi-Aventis 41, 121 Sanofi-Pasteur 121 Sartorius Stedim Biotech 86 Seattle Genetics 5, 14, 41, 51-52 Selventa 116, 118 Shire 8 Spirogen 51 Stada 73 Stanford University 98 STC Biologics 90 Stromedix 95 Swedish Orphan Biovitrum 20, 23 Symphogen 29, 60-62, 90, 93

T T2 Biosystems 103 TaiMed Biologics 121 Takeda 17, 21, 23, 26

Search 148 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Tanox 121 Targa 41, 49 TeGenero 7 TenX Biopharma 22, 27 Teva 73, 109 Thallion 121 Tolerx 92-93, 104-105, 107 Trion 55, 59, 105 Tufts 5, 19, 35, 90

U UCB 4, 21, 25 University Health Systems 108 University Hospital of Copenhagen 92 University of Cambridge 118 University of Eastern Piedmont 116 University of Leiden 27 University of Manitoba 81 University of New Mexico 116 University of Oslo 116 University of Toronto 116 UTSMC 41

V ViroPharma 8

W Watson 109 Wilex 22, 27 Wyeth 3, 46, 105

Search 149 Company Index The New Generation of Antibody Therapeutics: Current Status and Future Prospects

X Xcellerex 94 XOMA 28, 98

Z Zyngenia 59, 101-102

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Search 151 Cambridge Healthtech Institute Conferences www.healthtech.com For the past 18 years, Cambridge Healthtech Institute (CHI) has developed more than 1,000 conferences, which have attracted over 80,000 attendees from around the world. CHI is the industry leader in offering quality programs that provide valuable new insights and competing points of view while offering balanced coverage of the latest developments in the life science industry. Leading researchers and business experts from top pharmaceutical, biotech, and academic organizations present their most current findings in a forum that features panel discussions and audience participation. Each year, CHI organizes over 100 annual events geared to the biotech and pharmaceutical industries with specific focuses on Biomarkers, Genomics, Proteins and Proteomics, Drug Discovery & Development, IT and Informatics, Chemistry, Diagnostics & Safety, and Business. CHI’s flagship conference events include: • Discovery on Target • PEGS: The Essential Protein Engineering Summit • PepTalk: The Protein Science Week • Bio-IT World Conference & Expo • World Pharmaceutical Congress • Molecular Med Tri-Con

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