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Antibody Drugs

Overview

After more than 30 years of development, therapeutic antibody have become the fastest growing segment of global biopharmaceutical, and several "super blockbuster drugs" with annual sales of more than $5 billion have been born. As of June 2021, the Food and Drug Administration (FDA) has approved 104 antibody drugs, covering oncology, autoimmune diseases, cardiovascular and neurological diseases, anti-infection, rare diseases and other therapeutic areas. This article focuses on the types, development technology and clinical application of antibody drugs.

Characteristics of antibody drugs

  • Specificity
    • Specific binding of relevant antigens
    • Selective killing of tumor target cells
    • Targeted distribution in animals
    • Better efficacy for specific tumors
  • Diversity
    • Diversity of target antigen
    • Diversity of structure and activity of antibody
    • Diversity of immune conjugates and fusion proteins
  • Orientation of preparation
  • Antibodies with different therapeutic effects can be prepared according to needs.

Types of therapeutic antibodies

  • polyclonal antibody

Antibody Drugs Fig.1 Schematic overview of humanization
ratio of four monoclonal antibodies
(Lu RM et al. 2020)

Polyclonal antibodies (pAbs) are produced by heterogeneous mixtures of immune cells and can be obtained directly from the serum of immunized animals. Therefore, they can bind to different target epitopes of the same antigen. In this mixture, some antibodies bind to the target, while others bind to the off-target epitope, so the performance of different batches of polyclonal antibodies against the same antigen will be variable.

pAbs are relatively cheap and quick to produce, but once the cells are depleted, the same batch of antibodies cannot replicate. It has been widely used in research and diagnosis due to its high affinity, tolerance to small changes in antibodies (such as slight degeneration, polymorphism, heterogeneity of glycosylation, etc.) and robust detection ability.

  • Monoclonal antibody drugs

The structure of a typical antibody molecule consists of an immutable domain (C) that interacts with immune cells and a variable domain (V) that contains antigen binding sites. Four types of monoclonal antibodies have been developed on the market,1 and the composition of the two domains of these antibodies is also different. It is estimated that mouse, chimeric, humanized, and human monoclonal antibodies account for 2.8%, 12.5%, 34.7%, and 51%, respectively, of all monoclonal antibodies in clinical use. Human and humanized monoclonal antibodies are more frequently used in clinical treatment due to their low immunogenicity and high tolerance.

Antibody engineering technology

  • Murine monoclonal antibody

The hybridoma technique was first developed by Kohler and Milstein in 1975. This technique is to obtain a large number of monoclonal cell lines by continuous culture of myeloma cells in vitro, fusion of B lymphocytes that can secrete antibodies, and then screening and cloning of hypoxanthine aminopterin thymidine. This technique has laid the foundation for the development of therapeutic monoclonal antibodies. In the late 1980s, murine monoclonal antibodies began to enter the clinic.  However, in the process of application, mouse antibody was found to have obvious deficiencies, including allergic reaction, induction of anti-antibody, short half-life and weak binding with human Fc receptor, which restricted its clinical application.2

  • Chimeric antibody

In order to overcome the inherent immunogenicity and enhance the efficacy of monoclonal antibodies, new chimeric murine-human monoclonal antibodies have been developed by genetic engineering techniques.  The antigen-specific variable region of mouse monoclonal antibody can be transplanted into the constant region of human monoclonal antibody by genetic engineering, which can achieve about 65% humanization of mouse monoclonal antibody molecules.3 Chimeric monoclonal antibodies not only have lower immunogenicity, but also have a longer half-life in humans.

Antibody engineering technology

Fig.2 Antibody engineering technology (Lu RM et al. 2020)

  • Humanized antibody

By transplanting the hypervariable region of mouse antibody to the corresponding region of human antibody, the proportion of humanization of monoclonal antibody can reach 95%, which can overcome the deficiency of high immunogenicity of mouse antibody and chimeric antibody.4 The main limitation of humanized monoclonal antibodies is that the modification process is complex and time-consuming.

  • Fully human antibody

In vitro phage display technology and the emergence of transgenic animals carrying human variable regions have made it possible to produce full-human monoclonal antibodies. Phage display technology can isolate and control the specificity and affinity of monoclonal antibodies during the optimization of lead compounds. Combined with computational simulation and other antibody affinity maturation technologies, phage display technology is playing an increasingly important role in the development of monoclonal antibodies.

  • Bispecific antibody

Bispecific antibodies are engineered artificial antibodies capable of recognizing two epitopes of an antigen or two antigens.5 Currently, the most developed and studied bispecific antibody targets are CD3, PD1/PDL1, VEGF, HER2, CD47, EGFR, 4-1BB, CD20 and BCMA. Four bispecific antibodies have been approved for marketing worldwide.

Construction of several major bispecific antibody fragments

Fig.3 Construction of several major bispecific antibody fragments (Wang Q et al. 2019)

Clinical application of antibody drugs

COVID-19 antibody therapeutics: Since the COVID-19 pandemic began in late 2019, the biopharmaceutical industry has faced enormous challenges and opportunities.7

  • Bamlanivimab, casirivimab and imdevimab cocktail were authorized for emergency use by the US FDA
  • Levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively.

The proportion of antibodies used for cancer treatment Fig.5 The proportion of antibodies
used for cancer treatment
(Kaplon H.; Reichert JM, 2021)

Antitumor antibody drugs: Nearly 50% of the antibodies currently in clinical studies and on the market are used for cancer treatment. Listed antitumor antibody drugs involve more than 20 targets, and antibody drugs targeting popular targets such as PD-1/PD-L1, HER2, CD20, VEGF/VEGFR, EGFR occupy the majority of the market share.8

Antibody drugs for autoimmune diseases: It can be roughly divided into TNF, interleukin, integrin, B cell depletion and inhibition targets, and T cell depletion targets. TNF-α antibody drugs mainly include infliximab, adalimumab, percelizumab and fusion protein etanercept, which are used for the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease and other autoimmune diseases. Common targets of interleukin autoimmune diseases include IL-1, IL-2, IL-6/IL-6R, IL-7, IL-17A, IL-12, and IL-23.As the mechanisms of autoimmune diseases continue to be understood, new targets are gradually being discovered. In August 2021, the FDA approved Saphnelo (Anifrolumab- Fnia), Astra Zeneca's anti-type I IFN receptor antibody, for the treatment of moderate to severe systemic lupus erythematosus.10

Antibody drugs for other diseases: The FDA approved Aaducanumab in June 2021 for the treatment of early-stage Alzheimer's disease. In the area of cardiovascular disease, Alirocumab and Evolocumab, monoclonal antibodies targeting PCSK9, were approved by the FDA in 2015 for the treatment of familial hypercholesterolemia and hypercholesterolemia with statin intolerance.  In the area of central nervous system diseases, Biogen and Abb Vie's Daclizumab, targeting CD25, were approved for multiple sclerosis.

Summary and prospect

The development of mAb has experienced unprecedented growth since the first therapeutic mAb was approved 35 years ago. At present, therapeutic antibodies have become the dominant force in the biopharmaceutical market. The global market size of monoclonal antibodies is estimated to be USD 143.5 billion in 2020 and is expected to grow to USD 451.89 billion in 2028, with a CAGR of 14.1%.

Despite the shortcomings of early monoclonal antibody drugs, researchers have not given up the study of modification of monoclonal antibodies. Monoclonal antibodies can be further genetically engineered to improve affinity, stability, and biological activity. Advances in biotechnology will continue to drive the development of antibody drugs. There is no doubt that antibody drugs are changing the pharmaceutical industry and medical practice and offering new hope to patients who have failed conventional treatments. In the future, antibody drugs will still be used as a very effective treatment for disease treatment and research.

References:

  1. Lu, RM.; et al. Development of therapeutic antibodies for the treatment of diseases[J]. Journal of Biomedical Science, 2020, 27.
  2. Ober, RJ.; et al. Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies[J]. Int Immunol, 2001, 13: 1551–1559.
  3. Morrison, SL.; et al. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains[J]. Proc Nat Acad Sci USA, 1984, 81: 6851–6855.
  4. Jones, PT.; et al. Replacing the complementarity-determining regions in a human antibody with those from a mouse[J]. Nature, 1986, 321: 522–525.
  5. Wang, Q.; et al. Design and production of bispecific antibodies. Antibodies (Basel). 2019, 8(3):43.
  6. Kaplon, H.; Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13(1):1860476.
  7. Scott Andrew, M.; et al. Antibody therapy of cancer[J]. Nature reviews. Cancer. 2012, 12(4): 278-87.
  8. Frieder, J.; et al. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis[J]. Therapeutic Advances in Chronic Disease. 2017, 9(1):5.
  9. Furie, R.; et al. Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus[J]. Arthritis & Rheumatology, 2017, 69(2).

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