Monoclonal Antibodies As Neurological Therapeutics Part 1

Abstract: 

Over the last 30 years, the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. 

In recent years, monoclonal antibodies, as a new type of biological agent, have been widely used in the fields of anti-cancer, anti-inflammatory, and autoimmune diseases. With the deepening of monoclonal antibody research, people have gradually discovered that there is a close connection between monoclonal antibodies and memory.

First, monoclonal antibodies help improve memory. Studies have shown that monoclonal antibodies can improve brain function by promoting neuronal growth and enhancing neuronal connections. Monoclonal antibodies can also enhance the signal transmission of synapses in the brain to enhance learning and memory. Therefore, the application of monoclonal antibodies not only helps to treat diseases but also effectively improves human cognitive ability and memory.

Second, monoclonal antibodies can delay cognitive degeneration. As people age, the self-repair speed of brain cells gradually slows down, and the connection between brain cells gradually becomes loose. These changes ultimately lead to a decline in cognitive ability and memory degeneration. Monoclonal antibodies can delay the development of neurodegenerative diseases, especially the occurrence of cognitive disorders such as Alzheimer's disease, by maintaining the health of nerve cells and the connection between neurons.

Overall, the research on monoclonal antibodies is constantly expanding its application areas, and the connection with memory is one of the directions that people are exploring in depth. In the future, we believe that the research on monoclonal antibodies will further promote the development of cognitive neuroscience, thereby providing more and better cognitive rehabilitation programs for humans. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines, and neuromuscular disease. 

In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. 

Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. 

On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. 

This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease. 

Keywords: monoclonal antibodies; multiple sclerosis; migraine; neuromyelitis optica spectrum disorder; myasthenia gravis; Alzheimer's disease; inflammatory myopathies; immune-mediated peripheral neuropathies; Parkinson's disease; neurooncology; Duchene's muscular dystrophy

1. Introduction

The production of monoclonal antibodies (mAbs) was first described in 1975 when Köhler and Milstein developed methods for their isolation from hybridoma cells [1]. 

The ability to generate mAbs revolutionized antibody research and paved the way for tremendous clinical advances. For their discovery, Milstein and Köhler shared the 1984 Nobel Prize for Medicine or Physiology with Niels K. Jerne for "theories concerning the specificity in development and control of the immune system and discovery of the principle for production of monoclonal antibodies". 

According to the classical hybridoma method, mice were immunized with a mixture of antigens, their antibody-producing splenic B cells were fused with immortalized neoplastic B cells (myeloma cells) bearing a selection marker and the fused cells (hybridoma cells) were cultured in a selective medium. 

When visible colonies grew, their supernatants were screened for antibody production. 

For the first time, unlimited amounts of monoclonal antibodies specific for a single determinant could thus be produced in vitro. 

Köhler and Milstein did not patent their method, which facilitated the use of hybridoma technology by academics and the pharmaceutical industry for the generation of future potential therapies. 

At first, myeloma cells which retained the capacity to secrete their immunoglobulin products were used. Later, such fusion was replaced by myeloma variants that express only one endogenous chain so that the fused cells secreted primarily or exclusively the antibody of the desired specificity. 

Besides their huge impact on research and diagnostic applications including epitope-specific immunoblotting, immunofluorescence, and immunohistochemistry, mAbs played an important role in therapeutics, contributing to the treatment of cancer, autoimmune and infectious diseases. The first mAb approved by the FDA for human use was a murine anti-CD3 monoclonal antibody, muromonab (OKT3), used for the treatment of organ transplant rejection [2]. 

However, murine mAb-associated allergic reactions (immune reactions against proteins from different species) led to the development of chimeric antibodies in 1984 [3]. 

Chimeric mouse-human antibodies were produced by grafting the entire antigen-specific domain of a mouse antibody onto the constant domains of a human antibody using recombinant DNA techniques [3]. 

Rituximab, a mouse-human chimeric mAb against the B-cell lineage marker CD20 was the first to be approved in 1997 by the FDA for the treatment of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma [4]. 

Humanization of murine mAbs was achieved in the second half of the 1980s using CDR grafting methodology [5]. Later, the development of fully human monoclonal antibodies, in which both the variable region (Fab) and the constant region (Fc) are 100% human, was made possible through the advent of in vitro phage display technology and the generation of different mouse strains expressing human variable domains. 

Advanced antibody engineering technologies, such as phage display, affinity maturation, single B cell antibody technology, and human antibody mice are described in detail by Lu et al. [6]. The development of biosimilar mAbs has in many cases decreased the cost of treatment. 

Antibodies of all types (murine, chimeric, humanized, and human) have been approved by the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other national agencies for the treatment of several diseases. 

Since the approval of OKT3, the use of mAbs has progressively come to dominate therapeutics in all fields of medicine, including neurology. Many of the mAbs used in neurology today have been repurposed from their original indications for hematological neoplasias (e.g., alemtuzumab, ofatumumab, and rituximab) or rheumatological disease (e.g., tocilizumab) [4,7–9]. 

Other mAbs have been developed originally for neurological disease (e.g., ocrelizumab for multiple sclerosis or mAbs for migraine prophylaxis). Sixteen marketed mAbs are used in neurology primarily for neuroimmunological conditions and migraine (Table 1). 

Nevertheless, many more mAbs are in development for neuroimmunological and neurodegenerative conditions (Table 2). In this review, we discuss some key features of mAbs and provide an overview of the mAbs used in neurological diseases.

2. Nomenclature

The nomenclature of the mAb reflects features such as the proposed target, original host, modifications, and conjugation to other molecules. The International Nonproprietary Name (INN) guidelines published by the WHO in 2014 and 2017 describe the classification for mAb names [140,141]. 

The mAb names consist of a prefix, two substems (reduced to one substem in the 2017 document), and a suffix. The prefix is referred to as "random"; it is intended to provide a unique drug name. 

The substems designate the target (e.g., "ci" for cardiovascular, "so" for bone, "tu" for tumor) and the source (host) in which the antibody was originally produced (e.g.,"-o-" for murine "-xi-" for chimeric, "-zu-" for humanized, "-nu-" for fully human). 

The second substem (which specifies the source of the antibody and whether it is humanized or chimeric) was eliminated in 2017 [8]. This change only applies to mAb created after 2017. The suffix for all mAbs is "mab." 

Biosimilar mAbs are named as the reference drug followed by a four-letter suffix consisting of four unique and meaningless lowercase letters and separated from the reference name by a hyphen [142].

3. Basic Categories of Monoclonal Antibodies

3.1. Murine Antibodies

Murine antibodies are produced entirely from mouse protein and are the earliest mAbs developed. Due to the source of their production, they were recognized as allogeneic proteins, thus leading to polyclonal human anti-mouse antibody (HAMA) reactions, usually 2–3 weeks after their initial infusion [143]. HAMAs frequently had neutralizing action leading to rapid murine antibody inactivation or affected their pharmacokinetics promoting accelerated plasma elimination [144,145]. No murine mAb is currently in use in neurology.

3.2. Chimeric Antibodies

The serious limitations murine antibodies impose upon their clinical use, necessitated the development of new products with human components. Initially, the Fc portion of the antibody molecule, which dictates the functions of the antibody, was chemically exchanged with a human constant portion [146], giving rise to chimeric monoclonal antibodies. 

Chimeric mAbs contain 34% mouse protein in the variable region of the antibody, thus leading to a lower incidence of HAMA reactions compared to murine mAbs. 

Moreover, chimeric mAbs have a wide range of antigen specificities, increased cellular toxicity, and a beneficial pharmacokinetic and pharmacodynamic profile (longer half-life and increased affinity for the antigen) [147]. Rituximab and infliximab are the only chimeric mAbs currently in use in neurology (Table 1).

3.3. Humanized Antibodies

Advances in methods of molecular biology led to the development of humanized mAbs, which are 90% human, and only 10% mouse protein. Humanized mAbs are even less immunogenic compared to chimeric mAbs. 

Molecular techniques were used to further eliminate regions in the murine immunoglobulin chains that are not involved in the binding of antigens and to replace them with the corresponding human sequences. 

Complementarity-determining regions (CDRs) within the variable regions of both the heavy and light chains are of great importance in the binding specificity of the antibody. 

DNA fragments that correspond to the CDRs were grafted into the framework of human immunoglobulin genes using molecular methods [5]. Furthermore, the replacement of some amino acid residues in the constant regions with the corresponding amino acids of the mouse "parental" monoclonal antibody proved advantageous [148]. 

Humanized antibodies retain the specificity and binding affinity of the "parental" murine mAbs while being less immunogenic and acquiring biological functions of choice [149]. The great majority of mAbs in use or development for neurological indications are humanized mAbs (Tables 1 and 2).

3.4. Fully Human Monoclonal Antibodies

Peripheral blood lymphocytes or single cells derived from naïve and immunized donors were used to isolate immunoglobulin genes and to prepare libraries of plasmids with the cDNAs of heavy and light chains. 

The combinatorial libraries were used to transfect bacteria which, in turn, were seeded on appropriate drug-supplemented agar medium Colonies producing active antibodies were then detected and isolated [150]. 

Phage display and transgenic mice technologies made the production of 100% human mAbs possible [6]. Complete removal of murine components led to the production of mAbs that were mostly less immunogenic and, in many cases, improved their pharmacokinetic profiles slowing their clearance from plasma [147]. 

Erenumab and ofatumumab are fully human mAbs currently indicated for migraine prophylaxis and multiple sclerosis, respectively (Table 1). The human and murine components of murine, chimeric, humanized, and human mAbs are schematically presented in Figure 1.

4. Mechanism of Action

Mabs may act through several direct and indirect mechanisms and some MAbs confer multiple mechanisms of action on a target [15

4.1. Direct Mechanisms

Direct actions include antagonism of a soluble ligand or receptor, blockade of cell-cell interaction, agonism on a surface receptor activating certain signaling pathways within the target cell, or inducing cell death [152,153]. 

The simplest form of antibody activity occurs when the antibody binds a soluble ligand, a cell-bound ligand, or a cell receptor, and blocks the binding of the ligand to the receptor, thereby disrupting the downstream signaling mediated by that receptor-ligand interaction. 

Examples of this activity are the binding of fremanezumab, galcanezumab, and eptinezumab to the calcitonin gene-related peptide (CGRP) preventing it from signaling through the CGRP and Amylin-1 receptors [154,155]. Another approach is binding to a cell receptor in a non-agonistic manner to block ligand binding and activation of downstream signaling pathways as in the case of erenumab, which is an anti-CGRP receptor mAb [155]. 

Finally, cell-cell interactions between a cell-bound ligand and a cell-bound receptor on another cell can be blocked by mAbs, as in the case of natalizumab blocking lymphocytic transendothelial migration by binding to lymphocytic VLA-4 (CD49d) and preventing its binding to endothelial vascular cell adhesion molecule (VCAM) [55]. 

Agonistic mAbs mimic the activity of the normal ligand [151,156]. The agonist activity can occur when the antibody binds the receptor in a manner that mimics the binding of the natural ligand, resulting in antibody-mediated downstream signaling [156]. 

Alternatively, mAbs exert agonist activity on receptors such as the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors initiate programmed cell death [157].

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