INTRODUCTION — Immunoglobulin molecules (antibodies) are multifunctional components of the immune system. Antibodies facilitate numerous cellular and humoral reactions to a variety of antigens, including those of the host (self) and foreign substances.
Most antibodies produced as part of the normal immune response are polyclonal, meaning that they are produced by a number of distinct B lymphocytes, and, as a result, they each have a slightly different specificity for the target antigen (eg, by binding different epitopes or binding the same epitope with different affinities). However, it is possible to produce large quantities of an antibody from a single B cell clone.
Since 1985, approximately 100 monoclonal antibodies (mAbs) have been designated as drugs; new approvals continue to accrue. Available mAbs are directed against a large number of antigens and used for the treatment of immunologic diseases, reversal of drug effects, and cancer therapy. The World Health Organization (WHO), which is responsible for therapeutic mAb nomenclature, reported in 2017 that over 500 mAb names have been provided. (See 'Naming convention for therapeutic mAbs' below.)
This topic will provide an overview of therapeutic mAbs, including their mechanisms of action, production, modifications, nomenclature, administration, and adverse effects.
Separate topic reviews discuss clinical uses of polyclonal antibodies, including subcutaneous, intramuscular, and intravenous immune globulin products (SCIG, IMIG, and IVIG, respectively):
●SCIG and IMIG – (See "Subcutaneous and intramuscular immune globulin therapy" and "Immune globulin therapy in primary immunodeficiency".)
●IVIG – (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)
Separate reviews also discuss the basic principles of antibody genetics, immunoglobulin structure, and cellular and humoral immunity. (See "Structure of immunoglobulins" and "Immunoglobulin genetics" and "The adaptive humoral immune response" and "The adaptive cellular immune response: T cells and cytokines".)
NAMING CONVENTION FOR THERAPEUTIC mAbs — A uniform naming convention for mAbs has been developed and updated to facilitate global recognition of a unique name for each product. The name of the mAb specifies certain features such as proposed target, original host, modifications, and conjugation to other molecules. Naming rules from the International Nonproprietary Name (INN) expert group of the World Health Organization (WHO) were originally published in 1995 and have been updated periodically [1,2].
INN documents from 2014, 2017, and 2021 describe the classification for mAb names [1,3,4]. The mAb names consist of a prefix, two substems (reduced to one substem in the 2017 document), and a suffix (table 1).
●Prefix – The prefix is referred to as "random"; it is intended to provide a unique, distinct drug name.
●Substems – The substems (also called "infixes") designate the target (eg, "ci" for cardiovascular, "so" for bone, "tu" for tumor) and the source (host) in which the antibody was originally produced (eg, "u" for human, "o" for mouse), as well as modifications (eg, "-xi-" for chimeric, "-zu-" for humanized). The second substem (which specifies the source of the antibody and whether it is humanized or chimeric) was eliminated in 2017 [3]. This change only applies to mAb names created after mid-2017; names created before that time will not be altered.
The rationale for eliminating the second substem that specifies the host included several concerns, such as the large number of antibody names being created, the use of the species information as a marketing tool despite lack of scientific support for true clinically important differences, and conceptual ambiguities that led to confusion, especially related to chimeric and humanized antibodies [3,5,6]. Thus, mAbs named after mid-2017 may have longer prefixes and shorter substems.
●Suffix – For all mAbs developed before 2022, the suffix (also called stem) was "mab"; rare exceptions included a few of the earliest mAb products that were produced before the "mab" stem was established in 1990 (eg, muromonab-CD3 [OKT3], digoxin immune Fab).
In late 2021, an expanded collection of four suffixes was introduced to accommodate the increasing number of mAbs, to decrease sound-alikes, and to provide information about modifications to the immunoglobulin structure [4]. These suffixes are to be used instead of "mab" for mAbs developed from 2022 onward.
•The suffix "tug" is used for full-length unmodified immunoglobulins that recognize a single epitope (monospecific).
•The suffix "bart" is used for full-length monospecific immunoglobulins with engineered constant regions or any point mutation introduced by engineering. (See 'Fc region engineering' below.)
•The suffix "mig" is used for bispecific or multispecific immunoglobulins with any structure. (See 'Bifunctional antibodies' below.)
•The suffix "ment" is used for monospecific immunoglobulin variable region fragments. (See 'Fab fragments and single-chain antibodies' below.)
PRODUCTION METHODS AND SPECIAL MODIFICATIONS — mAbs are homogenous preparations of antibodies (or fragments of antibodies) in which every antibody in the product is identical in its protein sequence, and thus every antibody is expected to have the same antigen recognition site, affinity, biologic interactions, and downstream biologic effects. This distinguishes mAbs from polyclonal antibodies, which are heterogenous in protein sequence and recognize heterogeneous epitopes on an antigen.
Additional methods are used to modify and mass produce the mAb that is ultimately administered to patients as a medical therapy, as discussed in the following sections.
Initial antibody selection — A key to an effective mAb is the quality of the interaction between its hypervariable region (also called the complementarity-determining region [CDR]) and the target antigen. The choice of target antigen is usually based on the scientific understanding of disease mechanism and/or observation of disease-specific antibody effects in preclinical models or individual patients.
Also key to clinical efficacy and low toxicity are the downstream effects of antibody-antigen binding. These effects can be reduced by using antibodies that lack certain epitopes from foreign (eg, nonhuman) species, although immunogenicity of the mAb is complex (ie, it is not simply a matter of the number of amino acid residues).
Several approaches are used for the creation of antibodies that react with the desired target:
●Immunize an animal – An animal (typically a mouse or rat) may be immunized with the target antigen. This was the most popular (and the only technically feasible) method in the early days of mAb production. Candidate B cells for producing a therapeutic mAb with specificity for the target are obtained by harvesting spleen cells from the animal. An example of an mAb created by this method is muromonab-CD3 (Orthoclone OKT3).
A serious risk with this approach is that some individuals exposed to mouse antibodies develop an immune response to the mouse antibody sequence. The risk of an allergic response and/or reduced bioavailability of mouse mAbs limits their clinical use; once an individual develops a human-anti-mouse antibody, they generally cannot receive additional doses of the original mAb or other therapeutic mAbs with a similar murine sequence [7,8]. Thus, approaches were developed to engineer changes to the immunoglobulin molecule such as humanizing the antibody or creating a chimeric antibody; these are used in the majority of mAbs initially selected in animals. Mice have been engineered with human immunoglobulin loci in place of the endogenous mouse sequences, thus generating human antibodies in mice. (See 'Modifications' below.)
Humanized mice allow for development of mAbs that lack mouse heavy chains and have a repertoire more similar to that of the human immune system. Casirivimab and imdevimab are two recombinant human mAbs directed against non-overlapping epitopes of the spike protein receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated using genetically humanized mice [9].
●Obtain an existing antibody – An existing antibody against a target antigen can be isolated from a patient. This method is especially applicable to cancer therapeutics because removal of a tumor and/or regional lymph nodes is often used in routine treatment. These tissues can be used to harvest tumor-infiltrating lymphocytes. Existing antibodies can also be isolated from peripheral blood, bone marrow, or other lymphoid tissues such as the spleen or tonsils [10]. Examples of this method include various investigational mAbs against viruses such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [11]. Bamlanivimab, targeting SARS-CoV-2, was developed using an antibody from an individual who recovered from infection [12].
●Screen a library – A library of antibodies (constructed using molecular techniques or purchased) can be screened in vitro for binding to a target antigen. Libraries vary widely in their size and diversity. They can be generated using phage display or other combinatorial methods. With a phage display library, a large collection of sequences can be introduced into bacteriophage (a virus that infects bacteria) in a stoichiometry such that each bacteriophage clone produces a single antibody or antibody fragment [13]. The size and diversity of the library can be adjusted by the investigator. Larger more diverse libraries are more likely to produce a therapeutic mAb or an mAb fragment that has the highest affinity and specificity for the target antigen. Examples of therapeutic mAbs that were derived from a phage display library include adalimumab, raxibacumab, and belimumab [13].
Once an mAb with a desired specificity has been obtained, it must be produced in large quantities for therapeutic use. The earliest production technology was to create a hybridoma (a cell-cell fusion) in which the antibody-producing cell is fused with a partner cell that has been immortalized. The partner usually used is a myeloma cell (a malignant B cell) that will proliferate indefinitely in culture. For mAb production from a hybridoma, the myeloma cell line must be nonproductive; otherwise, the hybridoma would also produce the antibodies from the myeloma cell line.
Once candidate hybridomas have been generated, they must be screened for immortalization and antibody production. Screening for immortalization can be done using a method that takes advantage of a specialized growth medium (figure 1). In this method, the fusion myeloma cell line has a defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which permits a cell to use xanthine and guanine as nucleotide precursors rather than synthesizing them de novo [14]. A cell with this enzyme defect will survive unless it is cultured in the presence of an inhibitor of de novo nucleotide synthesis such as aminopterin, which will render it unable to make any purine nucleotides. When the candidate hybridoma cell lines are cultured in the presence of aminopterin, only the lines that have successfully fused and contain HGPRT from the fusion partner will survive because they can use hypoxanthine to make purine nucleotides. Thymidine is also added to the culture medium since its synthesis is inhibited by aminopterin. This selection medium is referred to as HAT medium (hypoxanthine, aminopterin, thymidine). Screening for antibody production can be done using an immunoassay on the cell supernatant for binding to the target antigen.
Other methods have been developed for immortalization such as transfection with an immortalizing virus or production in an immortal cell culture line such as Chinese hamster ovary (CHO) cells [10].
Mass production — Once a source of the desired mAb (hybridoma, cell line, or other system) has been established, production must be scaled up to accommodate clinical use. A requirement for several grams of mAb per patient is not unusual. mAbs are large multimeric proteins (typical molecular weight, approximately 150 kilodaltons [150 kD]), and their proper functioning requires a number of post-translational modifications, including glycosylation and formation of disulfide bonds [10]. Thus, a eukaryotic production system that carries out normal eukaryotic post-translational modifications is used.
The major method of mAb production is using cultured cells such as CHO cells [7]. Alternative eukaryotic cell lines for mAb production are under consideration, such as yeast, which grow faster than mammalian cells [7]. Quality controls and purification steps are used to ensure a homogenous product with defined potency that is free of endotoxin and/or host cell proteins. Potency is assayed using an immunoassay or a cell-based assay.
Modifications
Fab fragments and single-chain antibodies — The use of antibody fragments instead of full-length antibodies may enhance pharmacokinetic properties and/or the efficiency of penetration into tissues or tumor masses (since fragments are smaller) [13]. Fragments typically have a single valence (binding site) for the antigen, rather than two valences that are characteristic of full-length antibodies. The following types of antibody fragments have been created, typically using molecular biology techniques in the laboratory:
●Fragment antigen binding (Fab) – Also called Fab fragments; consist of a variable domain and the first constant region each of heavy and light chain.
●Single-chain variable fragment (scFv) – An scFv consists of a light chain and heavy chain variable region joined by a linker peptide.
●Single-domain antibody (sdAb) – An sdAb is an antibody fragment consisting of a light chain variable region or heavy chain variable region.
A popular method for producing these fragments is use of a phage display library that can be used to screen large collections of potential antibody fragments for their binding to the antigen and other desired properties [13]. (See 'Initial antibody selection' above.)
Fab fragments lack the Fc component of the antibody (the remainder of the heavy chain) and thus are not capable of interacting with Fc receptors or activating complement. They typically are not appropriate as monotherapy for indications that depend on cell killing. Examples of clinical applications include the following:
●Caplacizumab is an sdAb consisting of a bivalent variable-domain-only fragment with high affinity for von Willebrand factor (VWF). Its binding blocks the interaction between VWF and platelets, which plays a central role in microvascular thromboses such as those seen in patients with thrombotic thrombocytopenic purpura (TTP). Incorporation of caplacizumab into TTP therapy is discussed separately. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)
●Ranibizumab is a recombinant humanized Fab fragment that binds to and inhibits human vascular endothelial growth factor A (VEGF-A). Ranibizumab inhibits the binding of VEGF to its receptors and thereby suppresses neovascularization and slows vision loss. Ranibizumab is used in the treatment of some forms of age-related macular degeneration.
●Abciximab is an Fab antibody fragment derived from a chimeric human-murine mAb (7E3) that binds to platelet IIb/IIIa receptors, resulting in steric hindrance and thus inhibition of platelet aggregation. Abciximab has been used in unstable angina and reduction of thrombosis in various coronary stenting procedures. (See "Early trials of platelet glycoprotein IIb/IIIa receptor inhibitors in coronary heart disease", section on 'Abciximab'.)
●Certolizumab pegol is an Fab fragment directed against tumor necrosis factor (TNF)-alpha. It is thought to have reduced Fc-mediated side effects since it lacks an Fc portion. Since the absence of the Fc portion shortens its half-life, the fragment is conjugated to polyethylene glycol (PEG), which increases half-life and allows a dosing interval of once every two to four weeks. Certolizumab is used in Crohn disease and rheumatoid arthritis. (See 'Fc region engineering' below.)
Humanized and chimeric mAbs — mAbs originally derived from a nonhuman species (mouse, rat) can be "humanized" to various degrees by engineering amino acid substitutions that make them more similar to the human sequence. This is done using recombinant DNA technologies.
In principle, the more similar an mAb is to human-derived sequences shared among many individuals, the less likely it is to elicit an immune reaction against the mAb. Potential adverse effects of immunogenicity include infusion reactions and reduced efficacy, although these are not easily predicted. (See 'Infusion reactions' below and 'Resistance' below.)
However, not all amino acid residues or groups of residues are similar in their immunogenicity. Further, it has become increasingly challenging to clarify what constitutes a chimeric antibody versus what constitutes a humanized antibody (eg, how many amino acid residues need to be changed for an antibody to qualify as humanized), and definitions have evolved over time [6]. In general, humanized mAbs are those in which small but critical parts of the complementarity-determining region (CDR) are from non-human sources, but the larger constant regions of the immunoglobulin heavy and light chains are human-derived. Chimeric antibodies are generally those in which the Fc part of the immunoglobulin molecule (but not the CDR) is of a human sequence. In general, chimeric mAbs and humanized antibodies contain >65 and >90 percent human sequence, respectively. In addition, several technologies exist to generate fully humanized antibodies for therapeutic use.
Prior to mid-2017, an mAb that had been humanized was designated by inclusion of the stem "zu" in its name (eg, trastuzumab), and chimeric mAbs were designated as chimeric by the addition of "xi" (eg, rituximab). However, as noted above, ongoing issues with accurately classifying an mAb as humanized or chimeric and the potential for these designations to be used as a marketing tool in the absence of scientific support for reduced immunogenicity of the nonhuman components have led to the decision that antibodies named after mid-2017 will not contain the "zu" and "xi" stems in their generic names. (See 'Naming convention for therapeutic mAbs' above.)
Bifunctional antibodies — Bifunctional antibodies (also called "bispecific" antibodies) are mAbs in which two immunoglobulin chains of differing specificity have been fused into a single antibody molecule. This allows the antibody to bring two different antigens (eg, two proteins) into close physical proximity, which in turn may carry out a new function. Examples of bifunctional mAbs include the following:
●Emicizumab binds to two coagulation factors (factor IXa and factor X), taking the place of activated factor VIII (factor VIIIa) in the coagulation cascade (figure 2). This mAb is available for prophylaxis against bleeding in certain individuals with hemophilia A. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)
●Blinatumomab binds to CD3 on T cells and the cell surface protein CD19, present on precursor B cell acute lymphoblastic leukemia (ALL) cells, potentially recruiting cytotoxic T cells to kill the ALL cells. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)
●Catumaxomab binds to the T-cell surface molecule CD3 and epithelial cell adhesion molecule (EpCAM), a tumor cell surface marker; it also has an Fc region that can bind to an Fc receptor on macrophages, natural killer (NK) cells, or dendritic cells. This combination of antigen binding in a single molecule has the potential to recruit T cells and antigen-presenting cells to a tumor and to elicit an anti-tumor immune response. Efficacy was shown in malignant ascites; however, production was discontinued in the United States and Europe due to the company's insolvency. (See "Malignancy-related ascites", section on 'Tumor-targeted treatment'.)
Other bispecific mAbs are under development for a number of indications, including various tumor types and inflammatory conditions [15-17]. While most bifunctional antibodies are being developed to engage immune cells with tumor cells, other therapeutic strategies include linking a cell with a "payload" (such as a drug) or blocking signaling in a tumor microenvironment (eg, to inhibit PD-1 and CTLA-4) [18].
Drug or toxin conjugation — mAbs can be used to deliver a drug or a toxin to a specific site, which may be especially useful for cell killing in cancer therapy or antimicrobial applications. Drugs or toxins are typically attached to the immunoglobulin molecule using covalent binding to prevent their premature dissociation before reaching the target cell. Early-generation drug conjugates had heterogenous ratios of drug to antibody, but subsequent methods for ensuring more consistent stoichiometry have been developed, including engineered alternate amino acids that selectively bind the drug [19].
As examples:
●Moxetumomab pasudotox is a humanized mouse mAb that targets CD22 and has been conjugated to a toxic fragment of Pseudomonas exotoxin A. (See "Treatment of hairy cell leukemia", section on 'Moxetumomab pasudotox'.)
●Polatuzumab vedotin is a humanized mAb that targets CD79b (the B cell antigen receptor complex-associated protein beta chain) and has been conjugated to the dolastatin analog monomethyl auristatin E (MMAE) via a protease-cleavable linker that enhances stability in plasma. Dolastatin and MMAE inhibit microtubule assembly and act as mitotic inhibitors. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Clinical Trials'.)
●Brentuximab vedotin is an mAb that targets CD30 and has been conjugated to MMAE via a cleavable linker. (See "Treatment of systemic anaplastic large cell lymphoma", section on 'Brentuximab vedotin' and "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Antigenized antibodies — Antigenization is an investigational approach in which an mAb can be engineered to deliver an antigen (eg, as a vaccine). This is done by replacing part of the antibody polypeptide with a fragment of a microbial antigen. Any sequence can be inserted into various portions of the antibody molecule. Antigenized mAbs are potentially useful as vaccines since they have a longer serum half-life compared with the isolated antigen fragment and may be better tolerated than some microbial fragments.
The successful presentation of microbial peptides contained in antibody molecules has been shown in a variety of animal systems (eg, for influenza virus in mice) [20]. However, this potentially promising technology has not advanced beyond animal studies. For example, using recombinant DNA methods, a bovine herpes virus B cell epitope was grafted onto a bovine immunoglobulin molecule. This antigenized antibody was used to immunize cows and generate antibodies against the virus [21].
Fc region engineering — Antibody engineering does not focus exclusively on antigen specificity and avidity; there is also significant attention being paid to understanding the immunobiology of Fc regions of the antibody heavy chain and to engineering modifications of the Fc portion of mAbs. (See "Structure of immunoglobulins", section on 'Fc fragment'.)
Antibody Fc regions have several functions:
●They bind to Fc receptors expressed on immune cells (lymphocytes, neutrophils, monocytes, dendritic cells, and epithelial cells) [22]. This binding can trigger changes in the immune cells that lead to phagocytosis of the antibodies and/or activation of the immune cells. Activated immune cells generate antibody-dependent cellular cytotoxicity (ADCC) and/or produce cytokines.
●They can bind complement component C1q and activate the classical pathway of the complement cascade.
●For IgGs, they can influence (typically, increase) the half-life of the antibodies.
The specific properties of the Fc portion and which Fc receptors it binds can vary depending on antibody isotype (IgG, IgA, or IgM).
All approved therapeutic mAbs are IgG (most are IgG1), which has been well-characterized for effector functions, including complement fixation and half-life prolongation.
Fc receptors can be engineered to bind specific receptors on subpopulations of cells or to have specific glycoprotein modifications. For example, IgG1 is a strong activator of ADCC, and IgG3 effectively recruits complement; a fusion of these domains can generate an mAb with both effector functions (see 'IgG1 fusion proteins' below). This was done with the mAb ocrelizumab, which is used in multiple sclerosis. (See "Treatment of primary progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)
Other protein modifications of the Fc region can promote binding to the neonatal Fc receptor (FcRn), which increases half-life. FcRn fusions have been used in other settings as well, such as in recombinant clotting factors. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer-lasting recombinant factor IX'.)
For some therapeutic applications, it is preferable to ablate the Fc region that binds to Fc receptors by using the IgG2 or IgG4 isotypes as backbones instead of IgG1, (IgG2 and IgG4 have less interactions with receptors than IgG1). This has been done for the anti-PD-1 checkpoint inhibitors pembrolizumab, nivolumab, and cemiplimab, which are formatted on an IgG4 backbone. Nevertheless, IgG2 and IgG4 subclasses can still harbor Fc receptor activating functions. Further engineering of the Fc would eliminate these effects. Removing the heavy chain N-linked glycan eliminates most of the Fc receptor binding, a strategy used in the development of the IgG1 anti-PD-L1 inhibitor atezolizumab, used in lung cancer. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Atezolizumab'.)
In addition to engineering modified Fc protein structures, much attention has been placed on the glycosylation status of the Fc region, which may further influence effector functions and half-life. One major strategy is to remove a fucose at the conserved asparagine residue at position 297, which can significantly improve binding to FccRIIIa and FccRIIIb while maintaining low-affinity binding to the inhibitory FccRIIb. This modification is present in obinutuzumab, an anti-CD20 mAb lacking the fucose containing residue present in rituximab, resulting in more potent anti-B cell activity. In addition to carbohydrate residues, amino acids can also be modified to enhance activation via enhanced binding to FccRIIIa, as was done in re-engineered Ab against HER2, margetuximab. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Margetuximab'.)
Additional information about different Fc receptors on different cell types and mechanisms of complement activation and phagocytosis is presented separately. (See "Mast cells: Surface receptors and signal transduction" and "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Functions' and "Complement pathways" and "The adaptive humoral immune response".)
BIOSIMILAR mAbs — Biosimilar drugs are biologic therapies that are highly similar to the reference product in clinical potency and toxicity but may have slight differences in components that do not appear to affect their clinical efficacy or toxicity [23]. Biosimilar mAbs are being developed as the patents expire on existing products. Examples include mAbs similar to infliximab and adalimumab, which target tumor necrosis factor (TNF). Since mAbs have many functionalities, it is especially important to determine how potency, efficacy, and toxicity compare with the reference product. In the United States, pharmacists are not permitted to substitute approved biosimilar mAbs for the original biologic without first asking the prescribing physician, unless it has been specifically approved as an interchangeable product. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)
Biosimilar mAbs are named as the reference drug plus a four-letter suffix that consists of four unique and meaningless lowercase letters [24]. As an example, a biosimilar for the mAb infliximab is named infliximab-dyyb.
IgG1 FUSION PROTEINS — Immunoglobulin G1 (IgG1) fusion proteins (also referred to as Fc-fusion proteins) are biologic therapies that take advantage of some of the properties of the immunoglobulin Fc region such as enhanced half-life. IgG1 fusion proteins do not have an antigen-binding complementarity-determining region (CDR) and thus do not have a biologic target in the same sense that mAbs do, although the protein to which Fc is fused often does have a specific biologic function that is being manipulated.
The following are examples of IgG1 fusion proteins in clinical use:
●Etanercept is a fusion of two soluble tumor necrosis factor (TNF)-alpha receptors with the Fc portion of IgG. The two TNF receptors make it bivalent (ie, one etanercept molecule binds two TNF molecules). It is used to inhibit TNF-alpha in various immunologic and rheumatologic disorders. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'TNF inhibition'.)
●Recombinant human factor VIII fused to the Fc portion of IgG (rFVIII-Fc) is a form of factor VIII supplementation that can be used in individuals with hemophilia A. A corresponding product is available for hemophilia B (FIX-Fc). These fusion proteins have longer half-lives than the corresponding factor proteins without Fc fusion. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer lasting recombinant factor VIII' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer-lasting recombinant factor IX'.)
Some of these fusion proteins can be identified by the suffix "-cept"; others contain "Fc" in their names.
MECHANISM OF ACTION
General principles of mAb activity — mAbs are biologic substances, and, as such, each mAb may have unique aspects to its mechanism of action. The following discussion is an overview of the general principles of how therapeutic mAbs sequester or destroy their targets.
One of the key distinguishing attributes of mAbs is their affinity for the target antigen, which is determined by the variable region/complementarity-determining region (CDR). Antibodies with greater affinity can be selected in the laboratory. Affinity is quantified by calculating the association constant for binding between the antibody and a single monovalent antigen in vitro [25]. When the antibody is bivalent (eg, full-length), this affinity is amplified (eg, 1018 [a virtually irreversible binding reaction] rather than 109 L/mol). Antibody affinities are most often in the range of 105 to 1011 L/mol (picomolar to nanomolar affinity).
Another key attribute of mAbs is their ability to recruit other immune cells and molecules (such as complement), both of which can promote killing of target cells. This recruitment is mediated by the Fc (fragment crystallizable) portion of the antibody (figure 3), which includes the heavy-chain second and third constant regions.
Target is a cell surface antigen — The desired effect of an mAb directed against a cell surface antigen may involve blocking the function of a cell surface receptor or killing of the target cell.
●EGFR – In some cases the target antigen may be a cell surface receptor, and mAb binding may block the normal/physiologic ligand from binding the receptor, thus interfering with receptor function and in turn preventing cell proliferation or survival. Examples include mAbs directed against the epidermal growth factor receptor (EGFR) or the receptor tyrosine kinase erbB-2 (also known as HER2).
●CD20 – In other cases, the target may be a tumor cell or a B cell clone that produces an autoantibody (eg, an antiplatelet antibody in immune thrombocytopenia [ITP]). CD20 is a B cell surface marker targeted by mAbs including rituximab. The mechanism of cell killing may involve recruitment of complement proteins, phagocytes, or natural killer (NK) cells, which can promote immune-mediated destruction of the cell(s) expressing the target antigen on their surface.
Recruitment of immune mediators generally occurs through interactions with the Fc portion of the mAb. Fc receptors can modulate the cell killing effects of mAbs by recruiting immune effector cells to effect ADCC or antibody-mediated phagocytosis by monocytes/macrophages [26]. Fc receptors can also promote cell death via complement-dependent cytotoxicity (CDC), in which mAb binding to target cells results in the activation of the complement cascade.
Some antibodies have features of both ADCC and CDC, and in some cases, mAbs can be further engineered to alter their Fc binding to enhance cell death [27,28]. Complement activation can have both agonistic and antagonistic effects on CDC and ADCC, and it is unclear which mechanisms are most responsible for eliminating malignant cells. Target cell killing can also be enhanced by using the antibody as a vehicle to deliver a toxin or cytotoxic drug directly to the target cell using an mAb-drug or mAb-toxin conjugate. (See 'Fc region engineering' above and 'Drug or toxin conjugation' above.)
Investigational approaches are being tested for the generation of mAbs against intracellular proteins, an approach that could potentially expand available targets and methods of cell killing. Examples include engineering mAbs to be internalized by endosomal pathways [29].
Target is a plasma protein or drug — Antigen binding and sequestration of the protein away from its normal binding partners may be sufficient for the efficacy of an mAb directed against a soluble molecule such as a plasma protein or a medication.
Examples of plasma proteins that are targeted by mAbs include:
●Tumor necrosis factor (TNF) – Adalimumab, certolizumab pegol, golimumab, infliximab, and others (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'TNF-alpha antagonists')
●Vascular endothelial growth factor (VEGF) – Bevacizumab (see "Overview of angiogenesis inhibitors", section on 'Anti-VEGF antibodies')
Examples of drugs that are targeted by therapeutic mAbs include:
●Dabigatran (anticoagulant) – Idarucizumab (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal')
●Digoxin (antiarrhythmic agent) – Digoxin immune Fab (see "Digitalis (cardiac glycoside) poisoning", section on 'Antidotal therapy with antibody (Fab) fragments')
When bound to the mAb, these drugs are unable to interact with their normal targets and are essentially neutralized. They are eventually cleared from the body by macrophages, via Fc-mediated uptake and lysosomal degradation [30].
Target is an IgG receptor — Autoantibody-mediated disorders might be treated by reducing the length of time that IgG circulates [31]. The neonatal Fc receptor (FcRn) is the primary mechanism for increasing IgG half-life in the circulation, by promoting the recycling of IgG. The mechanism involves blocking the IgG binding site of the FcRn and thereby inhibiting IgG transcytosis, a process that is independent of the specificity of the IgG. (See "The adaptive humoral immune response", section on 'Nonopsonic Fc receptors'.)
Rozanolixizumab is an investigational mAb directed against the IgG binding region of FcRn that can reduce global IgG levels, potentially decreasing the activity of autoantibodies. It is under investigation for autoimmune disorders such as immune thrombocytopenia (ITP) and myasthenia gravis (MG) [32,33]. Concern has been raised for a possible increased risk of infection due to global reduction of total serum IgG levels but preliminary studies of short-term use suggest that infection rates are not increased. Rozanolixizumab does not affect the levels of other immunoglobulins (IgA, IgM, or IgE) or albumin. Efgartigimod is a human IgG1 antibody Fc-fragment that also inhibits the IgG binding site of FcRn and has similar encouraging results for ITP as Rozanolixizumab [34].
Target is an infectious organism — The use of mAbs directed against infectious pathogens is an area of investigation. The mechanism by which a therapeutic mAb protects against infectious diseases is similar to that of natural humoral immunity, although the details of microbe elimination are not completely defined. Potential uses include preventing or treating specific infections [35].
●Viruses – Most mAbs target proteins on the surface of a virus, thus neutralizing the virus from entering cells.
•Several mAbs target the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). These are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)'.)
•Palivizumab is an antibody against the respiratory syncytial virus (RSV) fusion (F) glycoprotein; it inhibits viral entry into host cells. This therapy was approved by the US Food and Drug Administration (FDA) for the prevention of RSV infection. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Palivizumab immunoprophylaxis'.)
•Investigational mAbs against HIV can improve immunity during active infection, with promising results in animal models using broadly neutralizing antibodies [35].
●Bacteria
•Some mAbs against bacteria can function both prophylactically and therapeutically (eg, by targeting the protective antigen domain of Bacillus anthracis or one of the Clostridioides difficile toxins). (See "Treatment of anthrax", section on 'Antitoxins' and "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Alternative therapies'.)
•mAbs include those targeting the conserved hemagglutinin A stem of Haemophilus influenzae were investigated but an effective mAb has not been developed.
As stated in a 2018 editorial, mAbs directed against pathogens are unlikely to be used routinely due to their high cost and requirement for parenteral administration; however, they may be especially useful for certain emerging infectious diseases [36]. Treatment of active disease and/or targeted prophylaxis might be especially important in individuals who have not been vaccinated against a pathogen but require immediate protection such as individuals infected with SARS-CoV-2 or Ebola virus, or pregnant women residing in Zika virus-endemic areas.
Therapeutic mAbs to treat COVID-19 were generated rapidly (within months) by sequencing B cells isolated from recovered patients. The clinical impact may be substantial.
INDICATIONS — Indications for mAbs are discussed in separate topic reviews on specific disorders. Some examples include the following:
●Hematologic malignancies – (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia" and "Initial treatment of stage II to IV follicular lymphoma" and "Initial treatment of acute promyelocytic leukemia in adults".)
●Solid tumors – (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
●Autoimmune disorders or disorders with an immune component – (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults".)
●Hypercholesterolemia – (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)
●Asthma – (See "Anti-IgE therapy", section on 'Omalizumab therapy in asthma' and "An overview of asthma management", section on 'Severe persistent (Step 4 or 5)'.)
●Osteoporosis – (See "Denosumab for osteoporosis".)
●Inflammatory bowel disease – (See "Overview of the management of Crohn disease in children and adolescents" and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)
●Allograft rejection – (See "Liver transplantation in adults: Overview of immunosuppression", section on 'Monoclonal antibodies' and "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection", section on 'Banff grade II or III rejection'.)
●Infectious organisms – (See "Treatment and prevention of Ebola virus disease", section on 'Ebola-specific therapies' and "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Alternative therapies' and "COVID-19: Management in hospitalized adults", section on 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)' and "Prevention of malaria infection in travelers", section on 'Monoclonal antibodies'.)
●Drug reversal – (See "Digitalis (cardiac glycoside) poisoning", section on 'Antidotal therapy with antibody (Fab) fragments' and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.)
These examples are only intended to provide a sense of settings in which an individual may be receiving a therapeutic mAb; they are not an exhaustive list. New indications for existing mAbs as well as new mAbs directed against additional target antigens are expected as disease mechanisms are elucidated, microbial antigens are identified, and new drugs are created.
ADMINISTRATION — Maintaining appropriate levels of the mAb requires a dose and administration schedule that takes into account the pharmacokinetics of the specific antibody and minimizes premature removal of the antibody (eg, by plasmapheresis).
Dose, route, and pharmacokinetics — Some mAbs are given in a fixed dose, and some are dosed according to body weight, as discussed in separate topic reviews. (See "Dosing of anticancer agents in adults", section on 'Newer targeted therapies and immunotherapy'.)
mAbs are proteins, so they are generally best administered parenterally. Some are administered intravenously (eg, infliximab), some can be administered subcutaneously (eg, emicizumab), and some can be administered by either route (eg, rituximab, in different formulations). Intramuscular use has also been reported (eg, palivizumab). The major determinants of the optimal administration route include the greater and more rapid bioavailability with intravenous use, balanced by avoidance of intravenous access for the subcutaneous route [37]. Antibodies injected subcutaneously are taken up by lymphatic channels and may not reach maximum plasma concentration for several days. Oral administration is being explored for certain intestinal indications. The mAb should be given by the route that was used to establish clinical efficacy and safety for the specific indication, unless given in the context of a clinical trial.
Once an mAb is in the circulation, it leaves the vasculature by hydrostatic and osmotic pressure, which may differ in different tissues [37]. Retention in tissues depends on affinity for the target. Most mAbs are eliminated by reticuloendothelial macrophages, via non antigen-dependent mechanisms. The half-lives of mAbs are quite variable, from two days to several weeks. Binding to the receptor FcRn (Fc-receptor of the neonate, expressed on many adult cell types) increases the half-life of human and humanized mAbs of the immunoglobulin G (IgG) class (see 'Modifications' above). The covalent attachment of polyethylene glycol (PEG) has been used to extend the half-life of an mAb (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Pegylated Fab' fragment'). The duration of biologic activity may differ substantially from the half-life due to different effects on and properties of the target cell.
As might be expected from the varying indications for mAbs and their diverse properties, the frequency of administration is mAb-dependent. As a general rule, antibodies are relatively stable in the circulation and can be given approximately once per week or at greater intervals. There are exceptions for which doses are given at more frequent intervals (eg, alemtuzumab, given in escalating doses on alternate days) or less frequent intervals (eg, rituximab maintenance therapy following treatment of a B cell malignancy).
Co-administration of more than one mAb — It is possible to co-administer more than one mAb, although this should only be done in situations in which they are being used to treat two different disorders, or, for a single disorder, if the combination has been demonstrated to have greater efficacy (or similar efficacy with reduced toxicity) than one of the mAbs alone. In principle, the mAbs could be directed against the same target, two different targets on the same cell, or two independent cell types.
Evidence for greater efficacy of two mAbs has been demonstrated in the following solid tumor examples:
●The combination of ipilimumab and nivolumab is used in melanoma for combined targeting of the costimulatory receptor cytotoxic T lymphocyte antigen 4 (CTLA4) and the immune checkpoint receptor program death 1 (PD-1), both of which are thought to augment the anti-tumor immune response. This combination has greater efficacy and greater toxicity (mostly gastrointestinal and hepatic) than either mAb alone. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)
●The combination of pertuzumab and trastuzumab is used in HER2-positive breast cancer, along with a taxane. Both mAbs target the HER2 receptor. The combination of both mAbs plus a taxane has greater efficacy and toxicity (eg, febrile neutropenia, diarrhea, skin changes) than trastuzumab plus a taxane but no increased rate of left ventricular dysfunction. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Trastuzumab plus pertuzumab plus a taxane'.)
Evidence for lack of a synergistic or additive effect has been demonstrated in trials in metastatic colorectal cancer that have evaluated combined treatment using the anti-epidermal growth factor receptor (EGFR) panitumumab together with mAbs that target the vascular endothelial growth factor (VEGF). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Dual antibody therapy'.)
Clinical trials testing other mAb combinations in other tumor types are ongoing [38].
Timing related to plasmapheresis or plasma exchange — Plasmapheresis and plasma exchange remove circulating proteins from the circulation, including mAbs. Thus, attention must be paid to the timing of administration of a therapeutic mAb with the plasmapheresis procedure.
Examples of conditions for which this consideration may be relevant include the following:
●Granulomatosis with polyangiitis (GPA) may be treated with plasmapheresis and rituximab. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Role of plasma exchange'.)
●Complement-mediated thrombotic microangiopathy (C-TMA; also called complement-mediated hemolytic-uremic syndrome [HUS]) may be treated with plasma exchange and eculizumab. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)
While plasmapheresis may remove a fraction of an mAb, there is evidence that certain mAbs may retain efficacy despite removal of a significant amount of the mAb, perhaps because the dose exceeds the capacity for complete removal and/or the interactions with the target occur with extremely rapid kinetics [39]. In addition, mAbs rapidly distribute beyond the intravascular space, so the amount of mAb removed by plasmapheresis is a fraction of the total tissue-distributed and target-bound mAb. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)
In other cases, removal of the mAb by plasmapheresis may be a desired effect. An example is an individual who has an adverse effect from an mAb such as progressive multifocal leukoencephalopathy (PML) from natalizumab; this may be reversed by performing plasmapheresis to decrease the concentration of natalizumab and restore immune effector function [40]. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Natalizumab'.)
If plasmapheresis is inadvertently performed immediately after administration of a therapeutic mAb, the treating clinician must decide whether it is necessary to administer another dose of the mAb or wait until the next scheduled dose. Often extra doses are not given. Factors to consider include the disease severity, number of doses administered previously, and time interval between administration of the mAb and initiation of the plasmapheresis procedure. In many cases, the sufficient quantities of the mAb may have reached their intended target despite removal of some of the antibodies during the plasmapheresis procedure.
In contrast to plasmapheresis, which removes plasma proteins, hemodialysis does not remove mAbs from the circulation.
ADVERSE EVENTS — mAbs are made using recombinant biotechnology. Thus, they do not carry infectious risks associated with polyclonal antibody products prepared from human plasma. However, they are biologic products and can elicit a number of immune-mediated and other reactions and adverse events (AEs) [41]. Thus, these therapies should not be prescribed without the requisite expertise in their use and appropriate facilities for treating potentially serious reactions. Individuals treated with mAb-based therapies should be made aware of potential AEs and given instructions to follow and contact information should they occur. The prescribing information for the specific mAb should be consulted for a complete list of AEs.
Infusion reactions — Infusion reactions are reactions that typically occur in the first one to two hours of starting an infusion. They can occur in response to biologic therapies such as mAbs as well as to other systemic therapies. They can affect any organ system and can range from mildly irritating injection-site reactions, increases in body temperature, or pruritus, to potentially life-threatening anaphylaxis. Mild reactions are common.
The immunogenicity of mAbs derived can lead to the development of anti-mAb antibodies, which are sometimes associated with acute hypersensitivity reactions. Even fully humanized mAbs can cause allergic reactions due to the presence of carbohydrate moieties on the heavy chain, such as occurs with cetuximab [42]. (See "Allergy to meats", section on 'Meats and monoclonal antibodies (cetuximab)'.)
While the majority of anti-mAb antibodies are immunoglobulin G (IgG) and can limit the availability and half-life of the drug, those of the IgE isotype can also mediate immediate swelling and anaphylaxis after repeated exposures. Strategies such as desensitization to modify these adverse reactions have been tried. Many times these acute hypersensitivity reactions can be confused with cytokine release syndromes (CRS), which are largely dependent on the amount and type of target cell rather than the characteristics of the therapeutic mAb. (See 'Cytokine release syndrome' below and "Cytokine release syndrome (CRS)".)
The management of infusion reactions depends on the severity of the reaction and the urgency needed for treatment of the underlying condition. Mild reactions can often be managed by early recognition and prompt intervention. Often, the mAb can be continued after temporarily stopping it; use of a slower infusion rate or concomitant therapy with antipyretics or antihistamines may be helpful. We typically give 25 mg of diphenhydramine intravenously, and if there is progression at 15 minutes we give an additional dose of 25 mg. Some protocols give 25 to 50 mg, reassess at 30 minutes, and give an additional dose if needed. Total doses of diphenhydramine should not exceed 100 mg in an hour. Institutional protocols and information specific to the disorder being treated should be consulted.
A separate discussion of infusion reactions to mAbs used to treat hematologic malignancies and solid tumors includes additional information about reactions to specific antibodies, along with recommendations for management, prevention, rechallenge, and desensitization. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)
Other immune-related AEs — In addition to infusion reactions, other immune-related AEs include a number of dermatologic, gastrointestinal, endocrine, and other inflammatory reactions related to alterations of the normal immune balance between immune activity and immune tolerance [41]. As an example, skin reactions may occur during the use of certain mAbs for cancer therapy. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)
In some cases, concomitant administration of an immunosuppressive medication such as a glucocorticoid may reduce these immune-related AEs.
Infections and autoimmunity are a potential risk after administration of any mAb that reduces immune function, including those that target antigens on B and T lymphocytes [8]. Some of these complications are discussed separately. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)
Cytokine release syndrome (CRS) is a severe immune reaction that may occur in individuals being treated for certain malignancies. (See 'Cytokine release syndrome' below.)
Undesired effects related to the target antigen — In some cases, AEs may be directly related to the biology of the target antigen. As examples:
●The mAb abciximab, which blocks platelet aggregation by blocking the function of platelet glycoprotein IIb/IIIa, can cause bleeding. (See "Early trials of platelet glycoprotein IIb/IIIa receptor inhibitors in coronary heart disease", section on 'Adverse effects'.)
●The mAb cetuximab, which inhibits epidermal growth factor receptor (EGFR), can cause dermatologic toxicity. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
●The mAb trastuzumab, which targets the HER2 receptor, can cause cardiotoxicity that is thought to be related to a role for HER2 in cardiomyocyte survival. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Pathophysiology of cardiotoxicity'.)
Cytokine release syndrome — CRS is a severe immune reaction that occurs in response to immunotherapy for certain cancers (eg, lymphoid malignancies), in which positive feedback leads to progressive elevation in inflammatory cytokines by T lymphocytes [8]. Typically it occurs within two to three days, up to 14 days after exposure to the inciting agent, although the time-course can vary depending on the cause. (See "Cytokine release syndrome (CRS)".)
It can occur in response to a therapeutic mAb or other immune-based therapies such as chimeric antigen receptor (CAR)-T cells. (See "Principles of cancer immunotherapy", section on 'Chimeric antigen receptors'.)
Some consider CRS an extreme form of an infusion reaction. CRS may be accompanied by fever, headache, nausea, malaise, hypotension, rash, chills, dyspnea, and tachycardia. Elevations in serum aminotransferases and bilirubin can be seen, and, in some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like syndrome have been reported. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Cytokine release syndrome (CRS)".)
The largest risk factor for CRS is tumor load. The antibodies most likely to cause CRS are those that promote T-lymphocyte activation. As examples:
●Blinatumomab, a bifunctional mAb that binds to the T-cell surface protein CD3 and the cell surface marker CD19, present on precursor B cell acute lymphoblastic leukemia (ALL) cells (see 'Bifunctional antibodies' above). In one series of 189 individuals treated with blinatumomab, 60 percent had fever, 28 percent had febrile neutropenia, and 2 percent had grade 3 CRS [43].
●Nivolumab, an mAb that binds to and inhibits the programmed death-1 (PD-1) protein that is expressed on T cells, B cells, and natural killer (NK) cells; its ligand (PD-L1) is expressed on tumor cells and is thought to interfere with cytotoxic T-cell effector function (see "Principles of cancer immunotherapy", section on 'PD-1 and PD ligand 1/2'). A case report has described CRS after a single dose of nivolumab in an individual with Hodgkin disease; the patient recovered, had a dramatic reduction in tumor size, and was able to receive additional doses [44].
●Rituximab, an mAb that targets CD20 on B lymphocytes, has been reported to cause CRS, particularly in individuals with B cell malignancies who have bulky disease. Rare cases of CRS associated with rituximab in other settings have been reported [45]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)
Prophylaxis for CRS (eg, premedication with acetaminophen and diphenhydramine) is sometimes incorporated into therapy protocols. Management of CRS depends on the severity (table 2) and may include interruption of the infusion, symptomatic treatment, intravenous fluids, and ventilator and/or pressor support [46]. The mAb tocilizumab, directed against interleukin (IL)-6, has been effective in treating CRS related to chimeric antigen receptor (CAR)-T cells, which, unlike an mAb, cannot be discontinued once they have been infused [46].
Interference with laboratory or blood bank testing — Therapeutic antibodies against CD38 such as daratumumab and isatuximab or against CD47 (magrolimab, previously called Hu5F9-G4) can interfere with the antibody screen used in pretransfusion testing by causing pan-agglutination. (See "Pretransfusion testing for red blood cell transfusion", section on 'Anti-CD38 mAbs (daratumumab and isatuximab)'.)
RESISTANCE — The concept of drug resistance is not usually applied to mAbs, but in some cases, it has been observed.
●In some cases, resistance is due to altered biology of the disease (eg, individual with cancer for whom an mAb was initially effective but later became ineffective).
●In other cases, reduced efficacy may be due to the development of neutralizing antibodies by the patient's immune system that are directed against the therapeutic mAb. This has been seen with certain mAbs, as discussed in separate topic reviews. Examples include mAbs directed against the following:
•Tumor necrosis factor (TNF)-alpha. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Anti-drug antibodies'.)
•Epidermal growth factor receptor (EGFR). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS/BRAF wild-type tumors'.)
•Proprotein convertase subtilisin/kexin type 9 (PCSK9). (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Immunologic and allergic effects'.)
It is important to note that not all alterations in cell signaling cause mAbs to become ineffective and not all anti-mAb antibodies cause the mAb to be neutralized.
PREGNANCY — Therapeutic mAbs are increasingly used to treat autoimmune diseases, which generally affect females of childbearing potential. The expanded and frequent use of these biologics, combined with their ability to improve health and thereby support conception and gestation, has underscored the need to investigate maternal and fetal safety.
Experience with administering mAbs during pregnancy is mostly limited to case reports. Most of these involve mAbs that have been approved for many years and therefore are of the IgG1 subclass, which can accumulate in the fetus.
IgG is poorly transported from the maternal blood to the fetus early in pregnancy, but by the middle of the second trimester, there is substantial increase in placental transfer of IgG1 and accumulation of maternal IgG in the fetal circulation. The neonatal Fc receptor (FcRn) is the critical receptor at the maternal-fetal barrier responsible for the transport of IgG (especially IgG1) to the fetal circulation. FcRn is expressed on the placenta within the syncytiotrophoblast layer. Via endocytosis, it promotes release of IgG into the fetal circulation [47]. FcRn normally is expressed in endothelial and liver cells and is the main regulator of the half-life of IgG, via endosomal recycling. Most mAbs can be transferred to the fetus via placental FcRn especially after the first trimester, and their effects on embryogenesis and fetal immune system development are unknown.
The most studied mAbs in pregnancy are the TNF-alpha inhibitors, used to treat rheumatoid diseases and inflammatory bowel disease. The role of TNF-alpha in embryogenesis and organogenesis has led to wide study for congenital birth defects after exposure to inhibitory mAbs. Many of the early studies were limited in differentiating outcomes between Mab drug exposure or insufficient disease control.
Evidence on the safety of TNF inhibitors comes from an analysis of postmarketing surveillance databases that identified 1850 pregnancies with exposure to a TNF-alpha inhibitor and found similar frequencies of spontaneous abortion, preterm labor, and low birth weight rates to the general population [48].
The 2016 European League Against Rheumatism (EULAR) recommendations for use of antirheumatic drugs before and during pregnancy stated that TNF inhibitors are reasonably safe to use in the first and second trimesters [49,50]. The American College of Rheumatology largely endorsed the use of certolizumab (which lacks an Fc receptor and does not bind the FcRn) and other IgG mAbs during the first and second trimesters [51]. Data on abatacept or tocilizumab during pregnancy are lacking, and most society guidelines recommend stopping treatment prior to conception or during pregnancy. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tocilizumab' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Abatacept'.)
B cells are a target for mAbs in systemic lupus erythematosus (SLE). Limited reports have not demonstrated concerns for congenital abnormalities with rituximab, although it has not been widely studied and is generally reserved for emergency use. Belimumab similarly has few reports that suggest a safe profile; however, its use is not encouraged during pregnancy [51]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Belimumab'.)
SUMMARY
●Scope and nomenclature – Numerous therapeutic monoclonal antibodies (mAbs) have been produced to treat an increasing number of medical conditions. The nomenclature has been standardized such that the name of the antibody provides information about the target and identifies the therapy as an mAb. Naming conventions have been updated (table 1) to account for technologic changes and distinction among sound-alikes. (See 'Naming convention for therapeutic mAbs' above.)
●Methodologies – Several technologies are available for selecting mAbs that recognize the target antigen and for producing the selected mAb for clinical use. Molecular engineering can be used to make further modifications, including generation of antibody fragments, humanization of antibodies produced in animals, generation of bifunctional antibodies that bring together two separate antigens, and/or conjugation of the mAb to a drug or toxin. (See 'Production methods and special modifications' above.)
●Mechanism of action – The mechanism of action for an mAb may involve immune modulation, cell killing, and/or neutralization of an infectious organism; this may be achieved by blocking a physiologic ligand-receptor interaction or by recruiting immune cells and proteins (eg, phagocytes, natural killer [NK] cells, complement) that can kill the target cell. In other cases, the mAb may act by sequestering a plasma protein or drug and preventing it from interacting with its ligand. (See 'Mechanism of action' above.)
●Indications – Clinical indications for mAbs include treatment of hematologic malignancies, solid tumors, immune disorders, hypercholesterolemia, asthma, osteoporosis, inflammatory bowel disease, and infections (including SARS-CoV-2); as well as bypassing the function of normal scaffold proteins and reversing the activity of a drug. Links to selected topic reviews that discuss these indications are provided above. (See 'Indications' above.)
●Administration – Important aspects of mAb administration include attention to the dose, route, and potential drug interactions; general principles are discussed above. In certain conditions, more than one mAb may be administered to the same patient. A patient can undergo plasmapheresis and receive an mAb, but the timing should minimize removal of the mAb by the plasmapheresis procedure. (See 'Administration' above.)
●Adverse effects – Potential adverse effects of certain mAbs include infusion reactions, cytokine release syndrome, immune-related effects, infections, autoimmunity, off-target effects, and interference with certain laboratory tests such as a type and screen. (See 'Adverse events' above and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)
●Resistance – Resistance to the therapeutic effects of mAbs is rare but can occur, either due to altered disease biology or to development of neutralizing antibodies by the patient's immune system. (See 'Resistance' above.)
●Related subjects – Separate topic reviews discuss therapeutic polyclonal antibody preparations including subcutaneous, intramuscular, and intravenous immune globulin (SCIG, IMIG, and IVIG). (See "Subcutaneous and intramuscular immune globulin therapy" and "Immune globulin therapy in primary immunodeficiency" and "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed to an earlier version of this topic review.
