Classification of Monoclonal Antibodies Used in Neurology
Primary Classification Framework
Monoclonal antibodies in neurology are classified into three main categories based on their mechanism of action: (1) agents targeting leukocyte migration into the CNS, (2) cytolytic antibodies that deplete specific immune cell populations, and (3) antibodies targeting cytokines, chemokines, and their receptors. 1
Category 1: Leukocyte Migration Inhibitors
- Natalizumab is the prototypical agent in this category, blocking α4-integrin to prevent leukocyte trafficking across the blood-brain barrier into the CNS 1, 2
- This mechanism directly reduces inflammatory cell infiltration into neural tissue, making it highly effective for relapsing forms of multiple sclerosis 2
- Natalizumab was the first monoclonal antibody approved for MS treatment and represents a major therapeutic achievement 3
Category 2: Cytolytic (Cell-Depleting) Antibodies
CD20-Targeting Agents (B-Cell Depletion)
- Rituximab, ocrelizumab, and ofatumumab target CD20-expressing B-cells, causing direct B-cell depletion through antibody-dependent cellular cytotoxicity and complement-mediated lysis 1
- Ocrelizumab is a recombinant humanized IgG1 monoclonal antibody with a molecular mass of approximately 145 kDa that specifically targets CD20 4
- These agents eliminate pathogenic B-cells that contribute to autoimmune inflammation in MS 1
CD52-Targeting Agents (Broad Immune Cell Depletion)
- Alemtuzumab targets CD52, causing profound and prolonged depletion of both T-cells and B-cells 1, 2
- This produces more extensive immunosuppression compared to selective B-cell depletion, with both greater efficacy and higher risk of secondary autoimmunity 2
Category 3: Cytokine/Chemokine Pathway Modulators
- Daclizumab targets the IL-2 receptor (CD25), modulating T-cell activation and expansion 1, 2
- Ustekinumab blocks IL-12 and IL-23 pathways by targeting their shared p40 subunit 1
- Atacicept and tabalumab target B-cell activating factors (BAFF/APRIL pathways) to reduce B-cell survival and antibody production 1
- Secukinumab targets IL-17A, blocking pro-inflammatory cytokine signaling 1
Alternative Classification: By Antibody Structure
Structural Nomenclature System
- The suffix "-mab" indicates monoclonal antibody, with preceding letters denoting the antibody's origin and target 5
- "-ximab" indicates chimeric antibodies (part mouse, part human protein) 5
- "-zumab" indicates humanized antibodies (predominantly human with small mouse-derived regions) 5
- "-umab" indicates fully human antibodies 5
Clinical Implications of Structure
- Humanized and fully human antibodies have lower immunogenicity risk compared to chimeric antibodies, reducing the likelihood of neutralizing antibody formation 5
- The degree of humanization affects both efficacy duration and safety profile, with more humanized forms generally better tolerated 5
Distinction from Neuronal Antibodies (Critical Pitfall)
Therapeutic vs. Pathogenic Antibodies
- Therapeutic monoclonal antibodies (natalizumab, ocrelizumab, etc.) are administered as treatment to modulate immune function 1
- Neuronal surface antibodies (NMDAR, LGI1, CASPR2, etc.) are pathogenic autoantibodies detected in patients that cause autoimmune neurological syndromes 6
Key Distinguishing Features
- Neuronal surface antibodies target synaptic receptors and are generally pathogenic through antibody-mediated mechanisms (receptor downregulation or complement-mediated damage) 6
- Onconeural antibodies (Hu, Ri, Ma2, amphiphysin) target intracellular antigens and serve as markers for paraneoplastic syndromes, with T-cell cytotoxicity as the primary pathogenic mechanism 6
- GAD antibodies target intracellular glutamic acid decarboxylase but do not generally associate with tumors and are considered markers of immune-mediated syndromes 6
Emerging Applications Beyond Multiple Sclerosis
- Monoclonal antibodies targeting CGRP (calcitonin gene-related peptide) represent a major breakthrough for migraine prevention, expanding the therapeutic scope of antibodies in neurology 3
- Experimental antibodies targeting misfolded proteins (amyloid-beta, tau) are in development for neurodegenerative diseases 3
- Antibodies blocking axonal growth inhibitors (Nogo-A, LINGO-1) are being investigated to promote neural repair and remyelination 3
Clinical Considerations for Neurologists
Target Specificity and Mechanism
- Monoclonal antibodies offer exceptional target specificity, minimizing non-specific effects compared to traditional immunosuppressants 5
- However, this specificity means each antibody has distinct class-specific and target-associated risks that must be understood 5
Blood-Brain Barrier Limitations
- A major challenge for therapeutic antibodies in neurology is their limited access to the brain parenchyma due to the blood-brain barrier 3
- This limitation is less relevant for antibodies targeting peripheral immune cells (like natalizumab blocking migration) versus those requiring CNS penetration 3