Established Drug Modalities Part 2: Monoclonal Antibodies
Article summary
Monoclonal antibodies (mAbs) are developed for various indications, with a focus in oncology. With over 100 FDA-approved entities, including blockbuster drugs like Keytruda and Humira, and evolving mechanisms of action, mAbs remain a core drug modality.
mAbs have unique features and mechanisms of action. They are characterized by their large size, monospecificity, and complex mechanisms of action, including high specificity for target molecules and the ability to engage immune system components, offering distinct advantages over other modalities.
Despite limitations like limited tissue penetration and potential immunogenicity, advancements in antibody engineering are expanding the therapeutic potential of mAbs, including the development of engineered antibody fragments for broader applications.
Monoclonal Antibodies: Pioneering Technologies and Therapeutic Triumphs
Monoclonal antibodies (mAbs) have emerged as a pivotal therapeutic modality, and their application has been enabled by key technological developments such as the hybridoma and humanization techniques. The hybridoma technique revolutionized antibody therapeutics development, allowing for the production of mAbs by fusing specific antibody-producing cells with immortalized myeloma cells. Concurrently, the humanization technique addressed the challenge of adapting antibodies from non-human sources for safe use in humans. More recently, mAbs are predominantly obtained through recombinant methods, marking a shift from traditional hybridoma approaches.
A milestone moment for therapeutic mAbs occurred in 1986 with the approval of muromonab, the first therapeutic monoclonal antibody by the FDA. Since then, mAbs have garnered immense success, witnessing approvals for over 100 distinct entities. Their applications span diverse therapeutic areas, including oncology, immunology, and infectious diseases. Notable therapeutic mAb examples include Keytruda and Opdivo –at the forefront of cancer immunotherapy, Dupixent and Stelara –addressing inflammatory diseases, and Humira –for immune disorders, all of which have achieved a blockbuster drug status.
mAbs are large proteins of about 150,000 daltons. They are characterized by a common Y-shaped structure, with the antigen-recognizing regions positioned at the tips of the Y (Figure 1). mAbs are composed of two identical heavy chains and two identical light chains. These chains contain variable (V) and constant (C) regions, with the V regions responsible for antigen recognition. A unique feature of mAbs is their monospecificity, as they are derived from a single clone of B cells. This ensures that all molecules have identical antigen-binding sites.
Figure 1. The structure of monoclonal antibodies (mAbs). A. Cartoon representation of a mAb. LC – light chain, in orange; HC – heavy chain, in red. B. The crystal structure of Keytruda (PDB code 5DK3). Secondary structures are show in cartoon representation. Colors as in A. Aspirin is shown to illustrate the difference in size between a small molecule drug and an antibody.
Advantages of Monoclonal Antibodies in Cancer Therapy: Enhanced Specificity and Increasing Complexity of Mechanisms of Action
A distinctive advantage of mAbs lies in their larger interaction surfaces present at their antigen-binding regions which bestows on mAbs exquisite specificity and high affinity for their target molecules. This specificity allows for a selective interaction with targets –for example targets predominantly present on cancer cells – while minimizing potential side effects from interacting with off-targets, making mAb therapies successful cancer immunotherapies.
Compared to small molecule drugs, mAbs can have more complex mechanisms of action. For example, by binding to a cell surface protein required for the survival of a cancer cell, mAbs can block the access to this protein and impact cancer cell viability and survival. This is the mechanism of action of immune checkpoint inhibitors, the discovery of which was awarded with a Nobel Prize in Physiology or Medicine in 2018. T-cells carry surface receptors that constantly sample the surface of other cells. When cells present a protein called programmed cell death ligand 1 (PD-1L) that is recognized by the T-cell receptor PD-1, they basically signal to the T-cell that they are healthy cells of normal tissue. Some cancer cells present large quantities of PD-1L on their surface. mAbs that recognize and bind PD-1L on cancer cells mask the ligand from T-cells, leading to the activation of T-cells and an immune response against the cancer cell. Additionally, the Fc region of mAbs (Figure 1) can engage immune system components, such as effector cells and complement proteins, contributing to antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, providing mAbs with more complex mechanisms of action, and giving them an edge in cancer therapies.
Immunogenicity, Bioavailability, and Cell Membrane Crossing: Considerations in Monoclonal Antibody Therapeutics
The relatively large size of mAbs tends to limit their tissue penetration. Further, because of their size and highly polar surfaces, antibodies typically cannot cross the cell membrane. For this reason, most mAbs are designed to target cell surface proteins or soluble extracellular targets. Nonetheless, exceptions exist, and advancements in antibody engineering continue to expand the boundaries of mAb applications, opening new possibilities for therapeutic interventions: several advanced and emerging antibody modalities represent engineered antibody fragments that preserve the specificity of mAbs but which are significantly smaller and penetrate tissues more effectively. For example, antibody derivatives like fragment antigen-binding (Fab) and single-chain variable fragment (scFv) antibody derivatives are significantly smaller than traditional mAbs, which allows them to penetrate tissues more effectively.
The relatively large size of mAbs can also make them immunogenic: the immune system can recognize them as foreign and trigger an immune response to eliminate them, limiting their efficacy. This limitation can be addressed via antibody humanization - a process in which non-human antibodies, typically derived from animals, are modified to make them more compatible with the human immune system by replacing sequences of the non-human antibody with corresponding human sequences, reducing immunogenicity and enhancing safety and efficacy for therapeutic use in humans. mAbs are also typically not orally bioavailable and require other types of administration into patients.
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