Therapeutic Antibodies in Medicine: An Overview

The field of antibody engineering has grown exponentially over the past 10-15 years. Initially sparked by the development of the first monoclonal antibody, this field now significantly impacts healthcare and diagnostics. Monoclonal antibodies have become vital tools in treating various diseases, including cancer and autoimmune conditions, and their role in diagnostics has also expanded.  

A fully functional antibody comprises four polypeptide chains forming a Y-shaped structure. Variants of antibodies include murine, chimeric, humanized, and camelid antibodies, each with unique properties and applications. Camelid antibodies, also known as VHH antibodies, are particularly notable for their small size and unique binding capabilities, making them suitable for targeted therapies.  

The journey of antibody therapeutics began with the first monoclonal antibodies, initially derived from murine models. The FDA approval of muromonab-CD3 marked a significant milestone, paving the way for many more therapeutic antibodies. Today, infliximab, adalimumab, trastuzumab, bevacizumab, and rituximab are some of the leading therapeutic antibodies used in treating cancer and autoimmune diseases. The nomenclature of antibodies, as outlined by the WHO, involves a prefix, a substem (indicating the target and host), and a stem (indicating the antibody type). Recent updates have streamlined these conventions and introduced distinct stems for different antibody types, including biosimilars. 

Antibody therapies can be categorized into three main types: 

1. Naked Antibodies: These kill target cells through antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). 

2. Immunoconjugates: These involve antibodies linked to radionuclides, drugs, toxins, or enzymes, enhancing their ability to target and kill cancer cells while sparing normal cells. 

3. Multistep Targeting: This includes bispecific antibodies and CAR-T therapies that enhance therapeutic effects by targeting multiple ligands or receptors.¹ 

The development of therapeutic antibodies has evolved significantly, moving from murine models to fully human antibodies using transgenic mice platforms. Early murine antibodies were immunogenic, leading to the development of chimeric and humanized antibodies to reduce this issue. Technologies like phage display have further enabled the creation of fully human monoclonal antibodies. 

Several databases provide comprehensive information on approved and investigational therapeutic antibodies. Notable resources include the Antibody Society, Oxford Protein Informatics Group, and Thera-SAbDab, which track antibody developments and offer valuable insights, particularly during the COVID-19 pandemic. 

Clinical Applications Across Medical Disciplines 

Hematological Diseases: Therapeutic antibodies have revolutionized hematology, with key antibodies like rituximab for CD20-targeted cancer treatments, emicizumab for hemophilia A, and crizanlizumab for sickle cell disease. Biosimilars are also being developed to make these therapies more accessible. 

Autoimmune Diseases: Antibodies targeting cytokines and cell receptors play a critical role in treating autoimmune diseases such as rheumatoid arthritis (e.g., tocilizumab), systemic lupus erythematosus (e.g., belimumab), and psoriatic arthritis (e.g., secukinumab). 

Cancer: Monoclonal antibodies have transformed cancer treatment, targeting immune checkpoints (e.g., nivolumab) and employing advanced techniques like antibody-drug conjugates (ADCs) and bispecific antibodies for enhanced therapeutic effects. 

Pulmonary Diseases: In respiratory medicine, antibodies like omalizumab for asthma and treatments targeting RSV and COVID-19 (e.g., palivizumab, bebtelovimab) have shown significant promise. 

Cardiovascular Diseases: Cardiovascular treatments include antibodies like alirocumab and evolocumab targeting PCSK9 to manage hyperlipidemia, while canakinumab addresses inflammation in cardiovascular disease. 

Renal Diseases: Antibodies such as rituximab are used for conditions like membranous nephropathy and ANCA-associated vasculitis. Eculizumab is effective in treating C3 nephropathy and atypical hemolytic uremic syndrome. 

Gastrointestinal Pathologies: In gastrointestinal medicine, TNFα inhibitors (e.g., infliximab) and anti-integrin mAbs (e.g., vedolizumab) are used for IBD, with novel therapies targeting PSC, NASH, and eosinophilic esophagitis. 

Infectious Diseases: The COVID-19 pandemic underscored the importance of monoclonal antibodies in infectious disease treatment, with examples including palivizumab for RSV and ansuvimab for Ebola. 

Endocrine Disorders: In endocrine disorders like type 1 diabetes, teplizumab targets CD3 to inhibit T-cell activation. Other antibodies like rituximab show promise in preserving β-cell function. 

Neurological Disorders: Neurological treatments include antibodies for multiple sclerosis (e.g., natalizumab), Alzheimer's disease (e.g., aducanumab), and migraines (e.g., erenumab). However, Parkinson's disease remains a challenge for antibody therapy. 

Ophthalmological Disorders: Ranibizumab and bevacizumab target VEGF to treat retinopathy of prematurity and other retinal conditions, showing promising results in clinical trials. 

Musculoskeletal Disorders: Antibodies like denosumab and romosozumab are used to treat osteoporosis, while eculizumab is effective in treating myasthenia gravis. 

Future Directions of Antibody Therapeutics 

The future of antibody therapeutics lies in miniaturization, multifunctionalization, personalized vaccines, and AI-driven design. Advances in bioinformatics and machine learning enhance the efficiency of antibody discovery and optimization, reducing immunogenicity and improving therapeutic outcomes. Emerging technologies like AI and machine learning are set to revolutionize antibody engineering by identifying common motifs and epitopes, predicting structural properties, and optimizing therapeutic designs. 

Therapeutic antibodies have become indispensable in modern medicine, offering significant benefits for treating various diseases and generating substantial revenue for pharmaceutical companies. The future of antibody therapeutics is bright, with ongoing research and technological advancements poised to address unmet clinical needs and pave the way for personalized medicine. By investing in drug discovery, disease mechanism research, and leveraging AI, the potential of therapeutic antibodies is limitless. 

References: 

1. Sharma, P., Joshi, R. V., Pritchard, R., Xu, K., & Eicher, M. A. (2023). Therapeutic Antibodies in Medicine. Molecules, 28(18). https://doi.org/10.3390/molecules28186438