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Next Generation Antibody Drugs: Pursuit of the 'High-Hanging Fruit'

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Next Generation Antibody Drugs: Pursuit of the 'High-Hanging Fruit' REVIEWS Next generation antibody drugs: pursuit of the ‘high-hanging fruit’ Paul J. Carter and Greg A. Lazar Abstract | Antibodies are the most rapidly growing drug class and have a major impact on human health, particularly in oncology, autoimmunity and chronic inflammatory diseases. Many of the best understood and most tractable cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development. In this Review, we focus on emerging and novel mechanisms of action of antibodies and innovative targeting strategies that could extend their therapeutic applications, including antibody–drug conjugates, bispecific antibodies and antibody engineering to facilitate more effective delivery. These strategies could enable the pursuit of difficult to hit, less well-understood or previously undruggable targets — the ‘high-hanging fruit’. Biosimilar antibodies Since the mid‑1990s, antibodies have grown steadily for each of the most widely pursued targets, namely, Antibodies produced using into a clinically and commercially successful drug class. B lymphocyte antigen CD20, epidermal growth fac‑ different clones and cell lines Over 60 antibody‑based drugs have been approved tor receptor (EGFR), human epidermal growth factor than the original approved for therapeutic use and are currently marketed, with receptor 2 (HER2; also known as ERBB2), programmed antibody product of identical (TABLE 1) amino acid sequence, often by worldwide revenues of ~US$89 billion in 2016 . cell death 1 ligand 1 (PDL1) and tumour necrosis factor a different manufacturer. Historically, the success rate of humanized and human (TNF), not including biosimilar antibodies or the Fc fusion antibodies from first‑in‑human studies to regulatory protein etanercept that targets TNF and lymphotoxin‑α. Blockbuster approval has been at least 15%1. Thus, many new anti‑ In several cases, different antibody drugs engage compo‑ A term used for body drugs are expected from the extensive pipeline of nents of the same pathway, such as a receptor or its cor‑ pharmaceuticals to refer to those drugs with annual over 550 antibodies in clinical development (J. Reichert, responding ligand. Overlap in the approved indications sales of at least US$1 billion personal communication), including more than 50 anti‑ for antibodies is even more widespread. For example, per year. bodies in phase III clinical trials2. at least nine antibody drugs targeting interleukin‑17A Immunoglobulin G (IgG) is the predominant (IL‑17A), IL‑17 receptor A (IL‑17RA), TNF, CD6 IL‑23 Mechanisms of action (MoAs). Specific biochemical molecular format used in current antibody drugs. A or a subunit shared by IL‑12 and IL‑23 are approved for interactions and biological few antibody conjugates (including those conjugated the treatment of different forms of psoriasis, whereas processes through which a drug to cytotoxic drugs, radioisotopes or polyethylene glycol seven or more antibodies targeting CD20, IL‑6R or TNF elicits its pharmacologic effects. (PEG)), antibody fragments and bispecific antibodies are indicated for rheumatoid arthritis. have also been approved (FIG. 1). The proportion of anti‑ This crowded marketplace for antibody drugs has bodies with non‑IgG formats is higher for antibodies created a strong incentive to develop second‑generation in early clinical development, although IgG still pre‑ antibodies that are substantially improved and well dominates3. At least 30 antibody drugs are indicated for differentiated from their first‑generation counterparts. use in oncology, including for the treatment of many The recent or pending patent expiration for several prevalent solid and haematological tumours (TABLE 1). so‑called blockbuster antibody drugs has motivated the An approximately similar number of antibodies are development of many biosimilar antibodies, including approved for the treatment of chronic inflammatory or a few that have already been approved4. In addition, Department of Antibody autoimmune diseases. A few antibody drugs are being cost‑effectiveness analysis is being increasingly applied Engineering, Genentech, Inc., used to treat patients in other areas of medicine includ‑ to assess the benefits of new drugs5. 1 DNA Way, South San ing cardiovascular disorders, infectious and ophthalmic Major factors affecting the development of anti‑ Francisco, California mecha‑ 94080, USA. diseases, osteoporosis, as well as transplantation. body drugs include the selection of antibody [email protected]; One consequence of the approval of so many anti‑ nisms of action (MoAs) that exploit the target biology, [email protected] body drugs is that most share a therapeutic target with known target biochemistry and adequate exposure of doi:10.1038/nrd.2017.227 at least one other antibody or protein therapeutic. For the target to active antibody (FIG. 2). Many of the most Published online 1 Dec 2017 example, there are three to six marketed antibody drugs tractable and best understood secreted or membrane NATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | MARCH 2018 | 197 ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Table 1 | Antibody drugs marketed for therapeutic use or undergoing regulatory review INN (trade 2016 Companies Antigens Antibody format Approved indications (or Proposed MoA highlights name) worldwide (dosing route) potential first indication) sales (US$ million) Oncology Mogamulizumab 18 Kyowa Hakko CCR4 Humanized, Adult T cell leukaemia or Depletes target cells by (Poteligeo) Kirin glyco-engineered lymphoma ADCC, afucosylated for IgG1, κ-chain (i.v.) increased ADCC Blinatumomab 115 Amgen CD3 and Mouse bispecific ALL Mediates formation of a T (Blincyto) CD19 tandem scFv: BiTE lymphocyte–tumour cell (c.i.v.) synapse that results in tumour cell lysis Rituximab 7,482 Roche/ CD20 Chimeric IgG1, Non-Hodgkin lymphoma, Depletes target cells by (Rituxan and Genentech, κ-chain (i.v.) CLL, rheumatoid ADCC, CDC and inducing MabThera) Pharmstandard arthritis, granulomatosis apoptosis with polyangiitis and microscopic polyangiitis Ofatumumab 46 Novartis CD20 Human, CLL Depletes target cells by CDC (Arzerra) mouse-derived and ADCC IgG1, κ-chain (i.v.) Obinutuzumab 199 Roche CD20 Humanized, CLL, follicular lymphoma Depletes target cells by (Gazyva) glyco-engineered ADCC, CDC, ADCP and IgG1, κ-chain (i.v.) inducing apoptosis; reduced fucosylation for increased ADCC Ibritumomab 11 Spectrum CD20 Mouse IgG1, Non-Hodgkin lymphoma Radiation from 90Y induces tiuxetan (Zevalin) Pharmaceuticals κ-chain; cellular damage 90Y-containing radioimmunocon- jugate (i.v.) Tositumomab 8 Novartis CD20 Mouse IgG2a, Non-Hodgkin lymphoma Radiation from 131I induces (Bexxar) λ-chain; cell death, possibly through 131I-containing ADCC, CDC and inducing radioimmunocon- apoptosis jugate (i.v.) Inotuzumab NA Pfizer, UCB CD22 Humanized IgG4, ALL The cytotoxin, calicheamicin, ozogamicin κ-chain; ADC (i.v.) induces dsDNA breaks, (Besponsa) leading to cell cycle arrest and apoptosis Brentuximab 544 Seattle Genetics, CD30 Chimeric IgG1, Hodgkin lymphoma, The cytotoxin, MMAE, disrupts vedotin (Adcetris) Takeda κ-chain; ADC (i.v.) systemic anaplastic large microtubules, leading to cell cell lymphoma cycle arrest and apoptosis; depletes target cells by ADCP Gemtuzumab NA Pfizer, Wyeth, CD33 Humanized IgG4, AML The cytotoxin, calicheamicin, ozogamicin Takeda, UCB, κ-chain; ADC (i.v.) induces dsDNA breaks, (Mylotarg) Celltech Group, leading to cell cycle arrest and PDL BioPharma, apoptosis Fred Hutchinson Cancer Research Center Daratumumab 572 Johnson & CD38 Human, Multiple myeloma Depletes target cells by CDC, (Darzalex) Johnson transgenic ADCC, ADCP and inducing mouse-derived apoptosis IgG1, κ-chain (i.v.) Ipilimumab 1,053 Bristol-Myers CTLA4 Human, Melanoma Binds and antagonizes (Yervoy) Squibb transgenic receptor; augments T mouse-derived lymphocyte activation and IgG1, κ-chain (i.v.) proliferation Cetuximab 1,555 Eli Lilly & Co., EGFR Chimeric IgG1, Colorectal cancer, head and Binds and antagonizes (Erbitux) Merck KGaA κ-chain (i.v.) neck cancer receptor; inhibits cell proliferation; induces apoptosis; sensitizes cells to chemotherapy and radiotherapy; decreases VEGFA production; depletes target cells by ADCC 198 | MARCH 2018 | VOLUME 17 www.nature.com/nrd ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Table 1 (cont.) | Antibody drugs marketed for therapeutic use or undergoing regulatory review INN (trade 2016 Companies Antigens Antibody format Approved indications (or Proposed MoA highlights name) worldwide (dosing route) potential first indication) sales (US$ million) Oncology (cont.) Panitumumab 785 Amgen, Takeda EGFR Human, Colorectal cancer Binds, antagonizes and (Vectibix) transgenic downregulates receptor; mouse-derived inhibits cell proliferation; IgG2, κ-chain (i.v.) induces apoptosis; decreases pro-inflammatory cytokine and VEGF production Necitumumab 15 Eli Lilly & Co. EGFR Human, Squamous NSCLC Binds, antagonizes and (Portrazza) phage-derived induces internalization and IgG1, κ-chain (i.v.) degradation of receptor; depletes target cells by ADCC; increases sensitivity to chemotherapy (in in vivo models) Nimotuzumab NA Biocon, PT Kalbe EGFR Humanized IgG1, Glioma, head and neck, Binds and antagonizes (TheraCIM, Farma, Ferozsons κ-chain (i.v.) nasopharyngeal and receptor; anti-angiogenic, BIOMAb-EGFR) Laboratories,
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