Resources>Blog>Monoclonal Antibodies: Evolution, Therapeutic Applications, and Future Directions
Monoclonal Antibodies: Evolution, Therapeutic Applications, and Future Directions
Biointron2025-02-05Read time: 8 mins
DOI: 10.3389/fimmu.2019.01598
Monoclonal antibodies (mAbs) have transformed modern medicine by providing highly specific therapies for cancer, autoimmune diseases, and infectious diseases. Their development traces back to key immunological discoveries that laid the groundwork for antibody-based therapies.
Historical Development of Monoclonal Antibodies
The concept of antibodies emerged in the late 19th century when Emil von Behring and Shibasaburo Kitasato demonstrated serum therapy for diphtheria, revealing the protective role of immune proteins. Paul Ehrlich later introduced the "side-chain theory," which described how antibodies recognize and bind specific pathogens. The structural elucidation of antibodies by Rodney Porter and Gerald Edelman in the 1950s further advanced the field, demonstrating the Y-shaped structure composed of heavy and light chains.
A major breakthrough came in 1975 when César Milstein and Georges Köhler developed hybridoma technology, a method to generate monoclonal antibodies by fusing B cells with myeloma cells. This technology allowed for the large-scale production of antibodies with high specificity and uniformity, revolutionizing diagnostics and therapeutics. Hybridoma-derived mAbs quickly became tools for research, leading to their clinical applications in the 1980s. The first FDA-approved therapeutic mAb, muromonab-CD3, was introduced in 1986 to prevent organ transplant rejection.
Since then, advances in recombinant DNA technology and antibody engineering have enabled the development of humanized and fully human mAbs, reducing immunogenicity and enhancing therapeutic efficacy. Novel techniques such as phage display and transgenic mice further improved the discovery and optimization of antibodies with higher affinity and specificity.
Monoclonal antibodies function through several mechanisms, depending on their target and therapeutic goal.
Antigen Neutralization – Direct binding to a specific antigen to block its interaction with receptors. Examples include pembrolizumab (anti-PD-1) and trastuzumab (anti-HER2).
Receptor Blockade – Preventing signaling pathways that promote disease progression, such as cetuximab (anti-EGFR) for colorectal cancer.
Antibody-Dependent Cellular Cytotoxicity (ADCC) – Engaging immune effector cells like natural killer (NK) cells to induce target cell death, a mechanism seen in rituximab (anti-CD20).
Complement-Dependent Cytotoxicity (CDC) – Activating the complement cascade to lyse target cells, used in mAbs like eculizumab (anti-C5).
Immune Checkpoint Inhibition – Enhancing immune system activation against tumors by blocking inhibitory signals, as seen in nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4).
Payload Delivery – Conjugating mAbs with cytotoxic drugs or radioactive particles to specifically target diseased cells, as in trastuzumab emtansine (T-DM1).
These diverse mechanisms make mAbs highly versatile for treating complex diseases with minimal off-target effects.
Cancer immunotherapy has been one of the most significant applications of mAbs. They have been developed to target tumor-associated antigens, including HER2, CD20, PD-1, and CTLA-4.
Rituximab (CD20-targeting mAb) – Used for B-cell lymphomas and autoimmune diseases.
Trastuzumab (HER2-targeting mAb) – Effective in HER2-positive breast cancer.
Nivolumab and Pembrolizumab (PD-1 inhibitors) – Revolutionized the treatment of melanoma, lung cancer, and other malignancies.
Atezolizumab (PD-L1 inhibitor) – Enhances immune system response against cancer cells.
Bispecific antibodies, such as blinatumomab (CD19/CD3), further expand mAb applications by engaging both T cells and cancer cells, facilitating targeted immune responses.
Autoimmune Diseases
Monoclonal antibodies are widely used to modulate immune activity in autoimmune diseases.
Infliximab and Adalimumab (TNF inhibitors) – Used for rheumatoid arthritis, Crohn’s disease, and psoriasis.
Rituximab (CD20-targeting mAb) – Effective in multiple sclerosis and systemic lupus erythematosus (SLE).
Zaire Ebola virus mAbs – Recently approved therapies such as Inmazeb and Ebanga target the Ebola glycoprotein.
The ability to generate virus-neutralizing mAbs rapidly has significant implications for pandemic preparedness.
Other Emerging Applications
Monoclonal antibodies are being explored for neurodegenerative diseases, such as aducanumab for Alzheimer’s disease. In cardiovascular medicine, PCSK9 inhibitors like evolocumab lower cholesterol by targeting lipid metabolism pathways.
Despite their clinical success, monoclonal antibodies are expensive to produce due to complex bioprocessing and purification steps. Traditional batch-based manufacturing is costly and time-intensive, prompting interest in outsourcing antibody production to contract research organizations such as Biointron.
Immunogenicity and Resistance
Humanized and fully human mAbs have reduced but not eliminated the risk of immunogenic responses. Patients can develop anti-drug antibodies (ADAs) that neutralize therapeutic mAbs, reducing efficacy. Combination therapies and modified antibody structures, such as VHH antibodies or antibody fragments, may address these limitations, in addition to humanization.
Regulatory and Accessibility Issues
While over 100 mAbs have been FDA-approved, accessibility remains a challenge, particularly in low-income regions. Biosimilars offer a potential solution by providing cost-effective alternatives without compromising efficacy.
Advancements in antibody-drug conjugates (ADCs) and bispecific antibodies are expanding the potential of mAbs. T-cell engaging bispecifics (e.g., blinatumomab) and immune checkpoint bispecifics (e.g., tebentafusp) are emerging as promising alternatives to conventional therapies.
Genomic and proteomic technologies enable precision medicine approaches, where mAbs are tailored based on patient-specific biomarkers. Companion diagnostics are increasingly used to identify patients who will benefit most from targeted therapies, improving treatment outcomes.
Instead of traditional infusion-based therapies, gene therapy-mediated mAb delivery could provide long-term antibody expression from a single treatment. Clinical trials are evaluating this approach for diseases such as HIV and certain cancers.
In addition, combining mAbs with chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors is a promising strategy to enhance anti-tumor responses. Future studies will optimize these approaches to minimize toxicity while maximizing therapeutic benefit.
Monoclonal antibodies continue to drive innovation in biomedicine, shaping the future of targeted therapies across diverse diseases. Ongoing advancements in antibody engineering, manufacturing, and clinical applications will further enhance their therapeutic potential.
Pucca, M. B., Cerni, F. A., Janke, R., Bermúdez-Méndez, E., Ledsgaard, L., Barbosa, J. E., & Laustsen, A. H. (2019). History of Envenoming Therapy and Current Perspectives. Frontiers in Immunology, 10, 1598. https://doi.org/10.3389/fimmu.2019.01598
