The development of monoclonal antibody (mAb) drugs has had a tremendous impact on the (bio)pharmaceutical industry since the first mAb was commercialized in 1986.1 The ability of these biomolecules to bind to and influence targeted cells has led not only to safer and more effective therapies, but medicines for previously untreated diseases. As of November 10, 2014, some 47 mAbs had been approved in the US or Europe.1 In 2017, there are 58 mAbs on the market2 and more than 50 mAb candidates being evaluated in late-stage clinical studies, with at least six to nine new products expected to receive approval each year for the near future.3
Rapid growth of the market is clearly occurring. Grand View Research predicts the global market for mAbs will expand from $85.4 billion in 2015 to $138.6 billion by 2024.4 Human-based mAbs, in particular, will grow at a high annual growth rate. Technology for the commercial production of mAbs is also improving, leading to accelerated development.
Monoclonal antibodies do have their limitations, however, and many biopharmaceutical companies are developing next-generation antibodies designed to overcome them. Not only are they seeking to improve the safety, specificity and potency of mAbs, they are looking to develop antibodies that are more manufacturable.5
Their potential to offer improved performance has attracted the attention of most biopharmaceutical companies. As a result, Visiongain estimates the global market for next-generation antibodies, including engineered antibodies, antibody-drug conjugates (ADCs), bispecific and multispecific antibodies, antibody fragments and antibody-like proteins (ALPs), as well as biosimilar antibodies, will reach $11.6 billion in 2020.6 A few products have already received approval.
While many next-generation antibodies are designed to treat various types of cancer, there are new candidates being developed for other indications ranging from infectious diseases to central nervous system disorders. Next-gen antibodies have the potential to treat any type of disease, according to Andrew Chan, Senior Vice President of Research Biology at Genentech.5 The new modalities being incorporated into next-gen antibodies not only offer improved performance over their monoclonal counterparts, they offer the potential for new mechanisms of action, allowing access to different targets and multiple targeting within the same molecule, according to Mike Riley, Vice President and General Manager at Catalent Biologics.5
In some cases, synergistic effects lead to better performance in one molecule than can be achieved using two separate mAbs, according to Tony de Fougerolles, Chief Scientific Officer with Ablynx. He also notes that unexpected biological functionality can be revealed and utilized that is not accessible with mAbs.5 Of course, each next-generation antibody technology must be evaluated on its own merit and offers its own set of advantages and disadvantages. Some of these technologies involve smaller changes to mAb structures for improved performance, but with no significant changes in functionality, while others involve new modes of action but consequently carry greater risk and require proof of viability and commercial feasibility.
Engineered antibodies consist of mAbs that have been modified in some way. For instance, in the approved drugs Gazyva® (obinutuzumab from Genentech) and Poteligeo® (mogamulizumab from Kyowa Hakko Kirin Co., Ltd.), glycoengineering was used to modify the fragment crystallizable (Fc), or back-end, region, which is responsible for interaction with the immune system.7 Other approaches include protein engineering and isotype chimerism. All three methods are intended to increase stability by extending
half-life and improve the efficacy/potency of traditional mAbs by increasing their antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and/or antibody-dependent phagocytosis (ADCP) activities.7 In addition to the development of novel next-generation antibodies, engineered antibodies are also being investigated as biobetters.
Roots Analysis predicts that glycoengineered antibodies will account for 84% of the antibody market by 2021, while Fc-protein engineering antibodies will account for 56% of the market by 2026. The market research firm also anticipates that Atezolizumab from Roche and Durvalumab from AstraZeneca/MedImmune will be blockbusters.7 Overall, the engineered antibodies market will expand at a compound annual growth rate (CAGR) of 40% between 2016 and 2026.7
Most engineered antibodies under development target oncology indications, but some are intended for the treatment of other indications, including asthma, chronic obstructive pulmonary disease, neuromyelitis optica, ulcerative colitis and hemolytic disease in newborns.7 Over 70 products are either marketed or in preclinical/clinical development.7 Examples of companies developing engineered antibodies include MacroGenics, arGEN-X, Celldex Therapeutics, Clovis Oncology, Five Prime Therapeutics Inc., Genmab, Immune Design, MorphoSys, TG Therapeutics and Zymeworks, as well as most major pharma firms (Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Roche/Genentech, Janssen, etc.). Other firms have developed proprietary glycoengineering technologies, including BioWa (POTELLIGENT®), Glycart (GlycoMAb), Glycotope (GlycoExpress™), ProBioGen (GlymaxX®) and Xencor (XmAb Fc).
MacroGenics, Inc., according to President, CEO and Director Scott Koenig, is one company pursuing protein engineering for the production of modified mAbs. This firm substitutes carefully selected amino acids in the Fc region to afford desired activities.5 Janssen, as an example of a large pharma company, is developing immunoglobulins (IgGs) with hyper-Fc activity for targeting pathogens, tumor cells and protease-resistant IgGs with a variety of potent Fc activities for targeting pathogens, the highly protease-rich tumor microenvironment and inflamed tissues that are high in protease activity.8
ADCs comprise a monoclonal antibody linked to a highly potent small molecule drug, allowing highly targeted delivery of toxic payloads to specific cells. The ability of ADCs to treat oncologic indications with minimal side effects has attracted significant attention, and today ADCs are also being investigated for many non-cancer indications. For these reasons, Azoth Analytics predicts the global ADC market will expand at a CAGR of nearly 22% from 2017-2022.9
Two second-generation ADCs — Kadcyla® (ado-trastuzumab emtansine from Genentech) and Adcetris® (brentuximab vedotin from Seattle Genetics) — with higher levels of conjugation, greater homogeneity and improved linker stability have already been approved and proven to be highly successful, and there are approximately 60 other ADCs in development in 2017.10 Third-generation ADCs under development are being designed to target more effective antigens and use more effective small molecule cytotoxics, yet present reduced toxicity issues, incorporate new linker chemistries and function via new mechanisms of action.10
Among the different types of next-gen antibodies, bispecific antibodies, along with ADCs, perhaps have the most potential for commercial success. The first trifunctional antibody (Removab®, catumaxomab from Fresenius Biotech and TRION Pharma) was approved in Europe in 2009. The bispecific antibody Blincyto® (blinatumomab from Amgen) was granted conditional marketing authorization in the EU in November 2015 and received FDA approval in July 2017.
Since December 2014, more than 120 bispecific molecules have entered into clinical development.11 Most target cancer indications, but some bispecific antibodies
are in development for non-oncological diseases, including rheumatoid arthritis, respiratory diseases and autoimmune diseases. Roots Analysis predicts the global market for bispecific antibodies will reach a value of $5.8 billion by 2024.12
As of 2015, over 60 different bispecific formats had been developed,13 such as
biXAbs® (Biomunex Pharmaceuticals), CrossMabs® and DutaMabs™ (Roche/Genentech), nanobodies (Ablynx), tandem diabodies (TandAb, Affimed), bispecific T-cell engager antibodies (BiTE®, Amgen), dual-variable-domain immunoglobulins (DVD-Igs™, Abbvie), Triomab® (TRION Pharma) and dual-affinity retargeting (DART®) technology (MacroGenics).
Bispecific and multispecific antibodies are effective because they combine two (or more) specificities for targeting within one molecule. As a result, one antibody-like molecule can bind two (or more) antigens on a single or multiple cells. They can be produced in many different ways and are believed to provide a cost-effective means for accessing novel mechanisms of action for addressing unmet medical needs.11 For these reasons they should have a broad range of clinical applications, according to Paul Carter, Senior Director and Staff Scientist for Antibody Engineering at Genentech.5
Although there have been a handful of next-generation antibodies approved, many remain in clinical development and have yet to be proven commercially viable. Because these antibodies are generally more complex than mAbs, they need to provide significant benefits compared to traditional mAb therapies. The greater the complexity, the greater the challenges for development and large-scale manufacturing; it is essential, according to Koening, to demonstrate both efficacy/performance and manufacturability.5 Managing the very high potency of many next-generation antibodies during both production and delivery is another issue. More sensitive analytical techniques are needed to detect the low levels of active drug substance for characterization and quality determinations. The high potency may, however, allow the use of new, advantageous delivery systems not possible with conventional mAbs. Developing safe, convenient and effective delivery systems that encourage medication adherence is a top priority in the industry today.5
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.