Overview of therapeutic monoclonal antibodies

INTRODUCTION — Immunoglobulin molecules (antibodies) facilitate numerous cellular and humoral reactions to a variety of antigens, including those of the host (self) and foreign substances.

Most antibodies in the normal immune response are polyclonal, produced by many distinct B lymphocytes, and they each have a slightly different specificity for the target antigen (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, hundreds of monoclonal antibodies (mAbs) have been designated as drugs; new approvals continue to accrue. 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 conventions' below.)

This topic presents an overview of therapeutic mAbs mechanisms of action, production, modifications, nomenclature, administration, and adverse effects.

Separate topic reviews discuss uses of polyclonal antibodies, including subcutaneous, intramuscular, and intravenous immune globulin products (SCIG, IMIG, and IVIG):

●SCIG and IMIG – (See "Subcutaneous and intramuscular immune globulin therapy" and "Immune globulin therapy in inborn errors of immunity".)

●IVIG – (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

Separate reviews also discuss the 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 CONVENTIONS — 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 the 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 [1,2].

INN updates from 2014, 2017, and 2021 describe the classification for mAb names [1,3,4]. These consist of a prefix, two substems (reduced to one substem in the 2017 document), and a suffix (table 1).

●Prefix – This is "random" and intended to provide a unique, distinct drug name.

●Substems (also called infixes) – These 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 was eliminated in 2017 [3]. This only applies to mAb names created after mid-2017; names created before that time contain a substem that specifies the source of the antibody and whether it is humanized or chimeric.

Concerns that led to elimination of the second substem included the large number of antibody names being created, use of the species information as a marketing tool despite lack of scientific support for clinical value, and confusing conceptual ambiguities related to chimeric and humanized antibodies [3,5,6].

●Suffix (also called stem) – For mAbs developed from 1990 to 2022, the suffix was "mab"; rare exceptions included early mAbs produced before the "mab" stem was established (muromonab-CD3 [OKT3], digoxin immune Fab).

In late 2021, a 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.

•Use "tug" for full-length unmodified immunoglobulins that recognize a single epitope (monospecific).

•Use "bart" for full-length monospecific immunoglobulins with engineered constant regions or point mutations introduced by engineering. (See 'Fc region engineering' below.)

•Use "mig" for all bispecific or multispecific immunoglobulins. (See 'Bifunctional antibodies' below.)

•Use "ment" for monospecific immunoglobulin variable region fragments. (See 'Fab fragments and single-chain antibodies' below.)

PRODUCTION METHODS AND SPECIAL MODIFICATIONS — mAbs are homogenous preparations of identical antibodies (or antibody fragments). Every antibody molecule in the product has the same antigen recognition site, affinity, biologic interactions, and downstream biologic effects. This distinguishes mAbs from polyclonal antibodies, which contain heterogenous protein sequences and recognize heterogeneous epitopes.

Initial antibody selection — mAb efficacy depends on the quality of the interaction between its hypervariable region (also called 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 patients.

Downstream effects are also key to efficacy and safety. Toxicity can be reduced by using antibodies that lack certain epitopes from nonhuman species, although immunogenicity of the mAb is complex and not simply a matter of the number of amino acid residues.

Several approaches are used:

●Immunize an animal – An animal (typically 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 an mAb with specificity for the target are obtained by harvesting spleen cells from the animal. Muromonab-CD3 (Orthoclone OKT3) was produced this way.

A serious risk is that some individuals will mount an immune response to the mouse antibody sequence. Once an individual develops a human-anti-mouse antibody, they generally cannot receive additional doses of the original mAb or other murine mAbs with a similar sequence [7,8]. Workarounds were developed to humanize the antibody or create a chimeric antibody; these are now used in most mAbs initially selected in animals. Mice engineered with human immunoglobulin loci in place of the endogenous mouse sequences have also been created. (See 'Humanized and chimeric mAbs' below and 'Fc region engineering' below.)

Humanized mice allow development of mAbs that lack mouse heavy chains and have a repertoire more similar to the human immune system. Casirivimab and imdevimab, mAbs developed to treat coronavirus disease 2019 (COVID-19), were generated from humanized mice [9].

●Obtain an existing antibody – An existing antibody can be isolated from a patient. This method is applicable to cancer therapeutics because a tumor and/or regional lymph nodes are often resected and 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]. This has been done with investigational mAbs against human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [11]. Bamlanivimab was developed using an antibody from an individual who recovered from COVID-19 [12]. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

●Screen a library – A library of antibodies can be purchased or constructed using molecular techniques (phage display or other combinatorial methods) and screened for binding to a target antigen. Libraries vary widely in size and diversity. With phage display, a large collection of sequences is introduced into bacteriophage (a virus that infects bacteria) to generate a single antibody or antibody fragment per clone [13]. Larger more diverse libraries are more likely to produce a product with the highest affinity and specificity. Adalimumab, raxibacumab, and belimumab were derived from phage display libraries [13].

Once an mAb with a desired specificity has been obtained, it must be produced in large quantities. The earliest method involved create a hybridoma (cell-cell fusion) containing the antibody-producing cell and an immortalized partner cell (often a malignant B cell from multiple myeloma) that proliferates indefinitely in culture. The partner cell line must be nonproductive; otherwise, the hybridoma would also produce the myeloma antibodies.

Candidate hybridomas must be screened for immortalization and antibody production.

●Immortalization – If the myeloma partner cell line lacks the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), it can only grow in media lacking the purines xanthine and guanine by synthesizing them de novo [14]. When cultured in growth media lacking these enzymes plus an inhibitor of de novo purine synthesis, the myeloma partner cell will die unless it successfully fuses with the antibody-producing partner cell that expresses HGPRT (figure 1). This selection medium is referred to as HAT medium (hypoxanthine, aminopterin, thymidine); it also contains thymidine because thymidine synthesis is inhibited by aminopterin.

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].

●Antibody production – Screening can be done using an immunoassay on the cell supernatant.

Use of AI in mAb design — Generating therapeutically significant mAbs using traditional methods involves an immense amount of screening through vast numbers of candidates to find the few antibodies that are eventually developed into a drug. Advances in machine learning and computational power have allowed scientists to accelerate protein design to predict and improve antibody function.

Neural networks termed "protein language models," which are similar to those used in generative artificial intelligence (AI), can be trained using a database of protein sequences to predict structure and potentially function.

In a 2023 study, models were trained using tens of millions of existing protein sequences to engineer and generate immunoglobulins with high "fitness" to improve antigen binding [15]. To identify mutations that could conceivably evolve, algorithms were used to learn patterns, and amino acid substitutions were selected and screened for improved fitness. A protein language model-guided method was used to create a tool that could predict and improve affinity maturation for seven antibodies. While traditional methods would entail random screening of tens of thousands of antibodies, remarkably, fewer than 20 variants of each antibody were found by this AI-based approach to increase binding affinities for most candidates. Some of the newly developed antibodies had up to 160-fold increased affinity, and others had improvements in thermostability and viral neutralization against Ebola virus or SARS-CoV-2, the virus that causes COVID-19.

Using these computational methods can potentially accelerate antibody discovery for previously hard-to-target antigens and accelerate the laboratory evolution of candidate antibodies for therapeutic use.

Mass production — A requirement for several grams of mAb per patient is not unusual. A eukaryotic production system is used to provide needed post-translational modifications including glycosylation and disulfide bond formation [10].

Most mAbs are produced in cultured cells such as Chinese hamster ovary (CHO) cells [7]. Yeast are a fast-growing eukaryotic cell under consideration [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 — Smaller antibody fragments may enhance pharmacokinetic properties and/or tissue or tumor penetration compared with full-length antibodies [13]. Fragments typically have one valence (binding site) for the antigen, whereas full-length antibodies contain two valences. The following types of antibody fragments have been created:

●Fragment antigen binding (Fab) fragments – Consist of a variable domain and the first constant region each of heavy and light chain.

●Single-chain variable fragments (scFv) – Consist of a light chain and heavy chain variable region joined by a linker peptide.

●Single-domain antibody (sdAb) – Consists of a light chain variable region or heavy chain variable region.

Screening a phage display library is a popular method for producing these fragments [13]. (See 'Initial antibody selection' above.)

Fab fragments lack the antibody Fc component (remainder of the heavy chain) and 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 precipitates microvascular thromboses 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 the binding of vascular endothelial growth factor A (VEGF-A) to its receptors, in turn suppressing neovascularization and slowing vision loss in 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, causing steric hindrance inhibiting platelet aggregation. Abciximab has been used in patients with myocardial infarction and coronary stenting procedures. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'GP IIb/IIIa inhibitors'.)

●Certolizumab pegol is an Fab fragment directed against tumor necrosis factor (TNF)-alpha; lack of the Fc portion is thought to reduce Fc-mediated side effects. Lack of the Fc portion shortens half-life; conjugation to polyethylene glycol (PEG) 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 and "Medical management of moderate to severe Crohn disease in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Hinge region modifications — While much attention has been focused on the antigen receptor binding (CDR3) and effector cell function (Fc) modifications of antibodies, other studies have engineered variant sequences in the hinge region of Ig and have uncovered mechanisms that can improve the function of therapeutic antibodies.

The hinge region links the two antigen binding sites in the Fab portion of the antibody with the Fc effector region in the heavy chain domain [16]. The length of the hinge region varies among the different classes and subclasses of immunoglobulins. Hinge modifications can be used to increase or decrease the flexibility of this region.

●Longer hinge region with greater flexibility – Among the four subclasses of IgG, IgG3 has a hinge region of up to 62 amino acids, which is fourfold longer than the other IgG classes. Functions attributed to the longer IgG3 hinge region are due in large part to increased flexibility, as well as altered Fab–Fab and Fab–Fc positioning. These changes allow for two epitopes to be linked or for an epitope to be brought into closer proximity to an immune cell.

Moreover, the longer hinge region of IgG3 appears better able to engage low abundance antigens, as well as improve access to epitopes that may be in altered configurations. Clinically, IgG3 is the most frequently identified subclass of broadly neutralizing anti-HIV antibodies. These antibodies harbor a more flexible hinge that is thought to help target less-accessible epitopes on the viral envelope.

In a 2016 study, bispecific anti-Env neutralizing antibodies were engineered by combining a flexible hinge domain of IgG3 to promote Fab domain flexibility, resulting in the hetero-bivalent binding to the Env trimer [17]. This engineered antibody still retained the functional properties of the IgG1-Fc and displayed increased viral neutralization activity and antiviral potency.

●Shorter hinge region with less flexibility – The hinge region can also be made less flexible to promote agonistic activities. As an example, IgG2 subtype anti-CD40 antibodies have been shown to promote agonistic activity for potential treatments in cancer immunotherapy [18]. Engineered sequences in IgG2 that promote disulfide shuffling in the hinge region result in a less flexible antibody with increased therapeutic activity. Importantly, the agonistic antibody activity is independent of the effector antibody Fc function, and FcgR expression in the microenvironment. These engineering strategies have potential to develop therapeutic mAbs that are not constrained by the Fc region activity and in this case promote CD40 signaling as part of an immune response.

Humanized and chimeric mAbs — mAbs originally derived from mouse and rat can be "humanized" to various degrees using recombinant DNA technologies to engineer amino acid substitutions that make them more similar to the human sequence. Several technologies exist to generate fully humanized antibodies.

In principle, the more similar an mAb is to human sequences shared among many individuals, the less likely it is to elicit an immune reaction against the mAb such as infusion reactions and reduced efficacy, although these are not easily predicted. (See 'Infusion reactions' below and 'Resistance' below.)

Not all amino acid residues or groups of residues have similar immunogenicity. Further, it has become increasingly challenging to clarify what constitutes a chimeric antibody versus a humanized antibody (how many amino acid residues need to be changed for an antibody to qualify as humanized), and definitions have evolved over time [6].

The following general definitions apply:

●Humanized mAb – An mAb in which small but critical parts of the complementarity-determining region (CDR) are from non-human sources, but the larger constant regions of the heavy and light chains are human-derived. Generally contains >90 percent human sequence.

●Chimeric mAb – An mAb in which the Fc part of the immunoglobulin molecule (but not the CDR) is of a human sequence. Generally contains >65 percent human sequence.

Prior to mid-2017, humanized mAbs were designated by the stem "zu" (eg, trastuzumab), and chimeric mAbs were designated by the stem "xi" (eg, rituximab). However, ongoing issues with accurate classification and use of these designations as marketing tools without scientific support for reduced immunogenicity led to the decision that antibodies named after mid-2017 will not contain the "zu" and "xi" stems in their generic names. (See 'Naming conventions' above.)

Bifunctional antibodies — Bifunctional (also called bispecific) antibodies contain two immunoglobulin chains of differing specificity fused into a single antibody molecule. They can recruit two different antigens (eg, two proteins or cells) into close physical proximity to carry out a new function.

●Hemophilia A – 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 used for bleed prophylaxis in hemophilia A. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

●Cancer – Antibodies that bind to CD3 on T lymphocytes and antigens on cancer cells can facilitate immune attack of the cancer cells. These therapies are referred to as bispecific T cell engagers (BiTEs). (See "Principles of cancer immunotherapy", section on 'Bispecific T cell engagers'.)

Examples include:

•Blinatumomab recruits T cells to CD19 on precursor B cell acute lymphoblastic leukemia (ALL) cells.

•Teclistamab recruits T cells to B cell maturation antigen (BCMA) on multiple myeloma cells.

•Catumaxomab recruits CD3 to the tumor marker epithelial cell adhesion molecule (EpCAM); it also has an Fc region that can bind Fc receptors on macrophages, natural killer (NK) cells, or dendritic cells, to generate an anti-tumor immune response. Efficacy was shown in malignant ascites; however, production was discontinued in the United States and Europe due to corporate insolvency. (See "Malignancy-related ascites", section on 'Tumor-targeted treatment'.)

Other bispecific mAbs are under development for various malignancies and inflammatory conditions [19-21].

While most bifunctional antibodies 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) [22].

Drug or toxin conjugation — mAbs can deliver a drug or a toxin to a specific site, which may be especially useful for killing cancer cells or microbes. Drugs or toxins are typically covalently attached to the immunoglobulin to prevent premature dissociation. Early-generation drug conjugates had heterogenous ratios of drug to antibody; subsequent methods for ensuring more consistent stoichiometry include engineered alternate amino acids that selectively bind the drug [23].

●Polatuzumab vedotin is a humanized mAb that targets CD79b (the B cell antigen receptor complex-associated protein beta chain) and is conjugated to the dolastatin analog monomethyl auristatin E (MMAE) via a protease-cleavable linker that enhances stability in plasma. Dolastatin and MMAE inhibit mitosis by blocking microtubule assembly. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Clinical trials'.)

●Gemtuzumab ozogamicin is a humanized anti-CD33 mAb (IgG4κ) covalently attached to a calicheamicin-derived payload that binds the DNA minor groove and causes double strand breaks. This is used for AML. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Gemtuzumab ozogamicin'.)

●Brentuximab vedotin is an mAb that targets CD30 and is conjugated to MMAE via a cleavable linker. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma" and "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)", section on 'Overview'.)

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 half-life compared with the isolated antigen fragment and may be better tolerated than some microbial fragments.

This approach has been tested in several animal systems (eg, for influenza virus in mice or bovine herpes virus in cows) but has not advanced beyond animal studies [24,25].

Fc region engineering — Modifications of the Fc portion of mAbs can also be engineered. (See "Structure of immunoglobulins", section on 'Fc fragment'.)

Antibody Fc regions have several functions:

●They bind to Fc receptors expressed on lymphocytes, neutrophils, monocytes, dendritic cells, and epithelial cells [26]. Binding can trigger phagocytosis of the antibodies and/or activation of the immune cells to induce antibody-dependent cellular cytotoxicity (ADCC) and/or cytokine production. (See "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Antibody-dependent cellular cytotoxicity'.)

●They can bind complement component C1q and activate the classical complement pathway. (See "Complement pathways".)

●For IgGs, they can influence (typically, increase) the half-life of the antibodies.

The properties of the Fc portion 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.

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'.)

●FcRn binding – 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'.)

●IgG subclass – For some applications, the IgG2 or IgG4 isotypes are preferable as backbones, as they have fewer 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 "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

●Glycosylation – Much attention has been placed on the glycosylation status of the Fc region, which may further influence effector functions and half-life. Removing a fucose at the conserved asparagine 297 residue can significantly improve binding to FccRIIIa and FccRIIIb while maintaining low-affinity binding to the inhibitory FccRIIb. This modification was made in obinutuzumab, an anti-CD20 mAb, resulting in more potent anti-B cell activity than the anti-CD20 mAb rituximab.

●Receptor binding – 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'.)

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 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 efficacy or toxicity [27].

Biosimilar mAbs are being developed as the patents expire on existing products such as 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 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 [28]. 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) take advantage of some of the properties of the immunoglobulin Fc region such as enhanced half-life but lack an antigen-binding complementarity-determining region (CDR) and thus do not have a biologic target in the same sense as mAbs, although the protein to which Fc is fused often does have a biologic function that is being manipulated.

Examples include:

●Etanercept fuses two soluble tumor necrosis factor (TNF)-alpha receptors with the Fc portion of IgG, creating a bivalent protein that binds two TNF molecules. It is used to inhibit TNF-alpha in various immunologic and rheumatologic disorders. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition'.)

●Recombinant human factor VIII fused to the Fc portion of IgG (rFVIII-Fc) is an enhanced half-life factor VIII for hemophilia A. A corresponding product is available for hemophilia B (FIX-Fc). (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 contain the suffix "-cept"; others contain "Fc" in their names. (See 'Naming conventions' above.)

MECHANISM OF ACTION

General principles of mAb activity — mAbs are biologic substances; each mAb may have unique aspects to its mechanism of action. General principles of their attributes include:

●Affinity – Affinity for the target antigen is determined by the hypervariable region/complementarity-determining region (CDR). (See "Structure of immunoglobulins", section on 'Hypervariable region/complementarity-determining region'.)

Antibodies with greater affinity can be selected. (See 'Initial antibody selection' above.)

Affinity is quantified by calculating the association constant for binding between the antibody and a single monovalent antigen in vitro [29]. Bivalent antibodies have amplified activity (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).

●Recruitment of immune mediators – mAbs can recruit immune cells and molecules such as complement, which can promote killing of target cells. This is mediated by the Fc portion of the antibody (figure 3), which includes the heavy-chain second and third constant regions.

Fc receptors can recruit immune effector cells to cause antibody-dependent cellular cytotoxicity (ADCC) or antibody-mediated phagocytosis by monocytes/macrophages [30]. 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 [31,32]. 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.)

Target is a cell surface antigen — mAbs can block cell surface receptors or kill target cells.

●EGFR – Blocking the epidermal growth factor receptor (EGFR) or the receptor tyrosine kinase erbB-2 (also known as HER2) can prevent the normal ligand(s) from binding and in turn prevent cell proliferation.

●CD20 – Binding CD20 on B cells can kill the cells by recruiting complement proteins, phagocytes, or natural killer (NK) cells.

Investigational approaches are being tested for 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 [33].

Target is a plasma protein or drug — Antigen binding and sequestration away from a normal binding partner may be sufficient for the efficacy of an mAb directed against a soluble molecule such as a plasma protein or a medication.

Protein examples 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')

Drug examples include:

●Dabigatran – Idarucizumab (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal')

●Digoxin – Digoxin immune Fab (see "Digitalis (cardiac glycoside) poisoning", section on 'Antidotal therapy with antibody (Fab) fragments')

When bound to the mAb, these drugs are essentially neutralized and are eventually cleared by macrophages, via Fc-mediated uptake and lysosomal degradation [34].

Target is an IgG receptor — Autoantibody-mediated disorders might be treated by reducing the length of time that IgG circulates [35]. The neonatal Fc receptor (FcRn) maintains IgG in the circulation by promoting IgG recycling.

mAbs that block the IgG binding site of the FcRn and can inhibit IgG transcytosis independent of the specificity of the IgG. (See "The adaptive humoral immune response", section on 'Nonopsonic Fc receptors'.)

●Rozanolixizumab is an mAb directed against the IgG binding region of FcRn that can globally reduce IgG levels. It is approved for myasthenia gravis (MG) and under investigation for other autoimmune disorders [36-38]. Concern has been raised for a possible increased risk of infection due to global reduction of total serum IgG levels, but in preliminary studies of short-term use, infection rates are not increased. Rozanolixizumab does not affect the levels of IgA, IgM, IgE, or albumin. (See "Chronic immunotherapy for myasthenia gravis", section on 'Rozanolixizumab'.)

●Efgartigimod alfa is a human IgG1 Fc-fragment that inhibits the IgG binding site of FcRn; it has been approved for MG [39,40]. Immunoglobulin concentrations in the plasma decreased after administration of efgartigimod to levels similarly seen after 5 sessions of plasma exchange. Use of efgartigimod in other autoimmune diseases including ITP has shown promising results [41]. (See "Chronic immunotherapy for myasthenia gravis", section on 'Efgartigimod'.)

Target is an infectious organism — mAbs against infectious pathogens are under investigation. Potential uses include infection prevention or treatment [42].

●Viruses – Most mAbs neutralize viral entry into host cells.

•Several mAbs were developed rapidly (within months) to target the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). Rapid evolution of viral variants and development of effective oral antiviral therapies led to withdrawal of the emergency use authorization for these products. (See "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)'.)

•Palivizumab is directed against the respiratory syncytial virus (RSV) fusion (F) glycoprotein; it was approved by the US Food and Drug Administration (FDA) for preventing RSV infection. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis'.)

•Investigational mAbs against HIV can improve immunity during active infection, with promising results in animal models using broadly neutralizing antibodies [42].

●Bacteria

•Bacillus anthracis protective antigen domain or Clostridioides difficile toxins. (See "Treatment of anthrax", section on 'Antitoxins' and "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Alternative therapies'.)

•mAbs 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 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 emerging infectious diseases [43]. Treatment of active disease and/or targeted prophylaxis might be especially important in individuals who have not been vaccinated but require immediate protection such as SARS-CoV-2 or Ebola virus, or pregnant individuals in Zika virus-endemic areas.

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/small lymphocytic lymphoma" 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 "Medical management of moderate to severe Crohn disease in adults".)

●Allograft rejection – (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection", section on 'Banff grade II or III rejection' and "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Initial therapy'.)

●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 'Limited role for antibody-based therapies (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 not an exhaustive list; new indications and new mAbs continue to be developed.

ADMINISTRATION — The dose and administration schedule depend on the pharmacokinetics of the specific antibody.

Route, dose, and pharmacokinetics — Some mAbs are given in a fixed dose, and some are dosed according to body weight. (See "Dosing of anticancer agents in adults", section on 'Newer targeted therapies and immunotherapy'.)

●Administration route – mAbs are proteins, so they cannot be taken orally, with the exception of oral administration being explored for certain intestinal indications. 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).

Major determinants of administration route include greater and more rapid bioavailability with intravenous use, balanced by avoidance of intravenous access for the subcutaneous route [44]. Antibodies injected subcutaneously are taken up by lymphatic channels and may not reach maximum plasma concentration for several days. 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.

●Dose and pharmacokinetics – Dosing is determined from clinical trials. The duration of biologic activity may differ substantially from the half-life due to longer-lasting effects on the target cell.

mAb half-lives 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 IgG mAbs. (See 'Modifications' above.)

•Covalent attachment of polyethylene glycol (PEG) can also be used to extend half-life. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Pegylated Fab' fragment'.)

Once an mAb is in the circulation, it leaves the vasculature by hydrostatic and osmotic pressure, which may be tissue-dependent [44]. Retention in tissues depends on affinity for the target. Most mAbs are eliminated by reticuloendothelial macrophages via non-antigen-dependent mechanisms.

●Dosing interval – Administration frequency also varies. 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 more frequently (alemtuzumab is given in escalating doses on alternate days) or less frequently (rituximab maintenance therapy following treatment of a B cell malignancy).

Co-administration of more than one mAb — More than one mAb can be co-administered, 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.

Examples of evidence for greater efficacy of two mAbs include:

●Malignant melanoma – Ipilimumab and nivolumab are used together in melanoma to target 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)'.)

●Breast cancer – Pertuzumab and trastuzumab is used together 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'.)

Lack of a synergistic or additive effect has been demonstrated in metastatic colorectal cancer trials evaluating 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 tumors are ongoing [45].

Timing related to plasmapheresis or plasma exchange — Plasmapheresis and plasma exchange remove proteins from the circulation, including mAbs. The timing between mAb administration and the plasmapheresis procedure should be coordinated to minimize mAb removal.

●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 atypical hemolytic-uremic syndrome [aHUS]) 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, certain mAbs may retain efficacy, perhaps because the dose exceeds the capacity for complete removal and/or the interactions with the target occur with extremely rapid kinetics [46]. 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'.)

If there is an adverse effect from an mAb such as progressive multifocal leukoencephalopathy (PML) from natalizumab plasmapheresis to decrease the concentration of natalizumab and restore immune effector function [47]. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

If plasmapheresis is inadvertently performed immediately after an mAb is administered, the treating clinician must decide whether to administer another dose of the mAb or wait until the next scheduled dose. Often extra doses are not given. Factors to consider include:

●Disease severity

●Number of doses administered thus far

●Time interval between administration of the mAb and initiation of plasmapheresis.

Often sufficient quantities of the mAb may have reached their intended target despite removal of some of the antibodies during the plasmapheresis procedure.

Hemodialysis does not remove mAbs from the circulation.

ADVERSE EVENTS — mAbs are made using recombinant biotechnology and 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) [48]. They should not be prescribed without the requisite expertise 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 contains a complete list of AEs.

Infusion reactions — Infusion reactions typically occur in the first one to two hours of starting an infusion. 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.

Anti-mAb antibodies are sometimes associated with acute hypersensitivity reactions. Even fully humanized mAbs can cause allergic reactions due to carbohydrate moieties on the heavy chain, such as occurs with cetuximab [49]. (See "Allergy to meats", section on 'Meats and monoclonal antibodies (cetuximab)'.)

●Clinical manifestations – Effects of anti-mAb depend on whether the anti-mAb is an immunoglobulin G (IgG) or IgE.

•IgG – Most anti-mAb antibodies are IgG, and their main effect is to limit the availability and half-life of the drug, although not all anti-mAb antibodies are neutralizing.

•IgE – IgE anti-mAb can also mediate immediate swelling and anaphylaxis after repeated exposures. Desensitization has been tried.

Many times these acute hypersensitivity reactions can be confused with cytokine release syndromes (CRS), which largely depend on the amount and type of target cell rather than the characteristics of the mAb. (See 'Cytokine release syndrome' below and "Cytokine release syndrome (CRS)".)

●Management – Interventions depend on severity of the reaction and urgency of treating 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 we give an additional dose of 25 mg if there is progression at 15 minutes. Some protocols give 25 to 50 mg, reassess at 30 minutes, and give an additional dose if needed. The total diphenhydramine dose should not exceed 100 mg in an hour.

•Institutional protocols and information specific to the disorder being treated should be consulted.

•Infusion reactions to mAbs used to treat hematologic malignancies and solid tumors are discussed separately. (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 dermatologic, gastrointestinal, endocrine, and other inflammatory reactions related to alterations of the normal immune balance between immune activity and immune tolerance [48]. In some cases, concomitant administration of an immunosuppressive medication such as a glucocorticoid may reduce these immune-related AEs.

●Skin reactions – 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".)

●Infections and autoimmunity – mAbs that reduce immune function, including those that target antigens on B and T lymphocytes, can cause infections or autoimmune complications [8]. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)

●CRS – This 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:

●Abciximab, which blocks platelet aggregation, can cause bleeding. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'GP IIb/IIIa inhibitors'.)

●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".)

●Trastuzumab, which targets the HER2 receptor, can cause cardiotoxicity, 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 in response to immunotherapy for certain cancers, especially 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 (maximum 14 days) after exposure to the inciting agent, although the time-course can vary. (See "Cytokine release syndrome (CRS)".)

Some consider CRS an extreme form of an infusion reaction, with fever, headache, nausea, malaise, hypotension, rash, chills, dyspnea, and tachycardia. Elevated serum aminotransferases and bilirubin can be seen; disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis (HLH)-like syndrome have been reported. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Cytokine release syndrome (CRS)".)

●Risk factors – The largest risk factor for CRS is tumor load.

CRS can occur in response to an mAb or other immune-based therapies such as chimeric antigen receptor (CAR)-T cells. (See "Principles of cancer immunotherapy", section on 'CAR-T cells'.)

mAbs most likely to cause CRS are those that promote T-lymphocyte activation, such as:

•Blinatumomab, a bifunctional mAb that binds CD3 on T-cells and CD19 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 [50].

•Nivolumab, an mAb that binds to and inhibits the programmed death-1 (PD-1) protein 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 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 [51].

•Rituximab, an mAb that targets CD20 on B lymphocytes, has been reported to cause CRS, particularly in individuals with B cell malignancies and bulky disease. Rare case reports have described CRS with rituximab for non-cancer indications [52]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

●Prevention – Prophylaxis with acetaminophen and diphenhydramine is sometimes incorporated into therapy protocols.

●Treatment – Management of CRS depends on the severity (table 2) and may include [53]:

•Interrupting the infusion

•Symptomatic treatment

•Intravenous fluids

•Ventilator and/or pressor support

Tocilizumab, an mAb against interleukin (IL)-6, has been effective in treating CRS from CAR-T cells, which, unlike an mAb, cannot be discontinued once they have been infused [53].

Interference with laboratory or blood bank testing — mAbs against CD38 such as daratumumab and isatuximab or against CD47 (magrolimab) can interfere with the antibody screen used in pretransfusion testing by causing pan-agglutination. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Anti-CD38 (daratumumab, isatuximab)'.)

RESISTANCE — Drug resistance usually does not apply to mAbs, but it has been observed.

●Resistance may be due to altered biology of the disease (eg, individual with cancer for whom an mAb was initially effective but later became ineffective).

●Reduced efficacy may be caused by neutralizing antibodies generated by the patient's immune system. This has occurred with:

•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')

However, not all alterations in cell signaling reduce mAb efficacy and not all anti-mAb antibodies are neutralizing.

PREGNANCY — mAbs are increasingly used to treat autoimmune diseases that affect females of childbearing potential, necessitating investigations of maternal and fetal safety.

Experience during pregnancy is mostly limited to case reports, generally involving 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 and promotes release of IgG into the fetal circulation via endocytosis [54]. 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 tumor necrosis factor (TNF)-alpha inhibitors. 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.

Analysis of postmarketing surveillance databases 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 [55].

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 [56,57]. 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 [58]. 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 [58]. (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 – Therapeutic monoclonal antibodies (mAbs) are available to treat an increasing number of conditions. Nomenclature is standardized, and naming conventions have been updated (table 1). (See 'Naming conventions' above.)

●Methodologies – Several technologies are available for selecting and producing mAbs for clinical use. Modifications include generation of antibody fragments, modification of the hinge region, humanization of antibodies produced in animals, creation of bifunctional antibodies that recruit two separate antigens, and conjugation to a drug or toxin. Artificial intelligence (AI)-based methods for antibody design are under study and show promise in accelerating mAb discovery. (See 'Production methods and special modifications' above.)

●Mechanism of action – mAbs can modulate immunity, kill cells, and/or neutralize infectious organisms. Mechanisms include blocking a physiologic ligand-receptor interaction and recruiting immune cells and proteins (eg, phagocytes, natural killer [NK] cells, complement) that can kill the target cell. mAb can sequester plasma proteins or drugs away from their ligands. (See 'Mechanism of action' above.)

●Indications – mAbs are used for hematologic malignancies, solid tumors, immune disorders, hypercholesterolemia, asthma, osteoporosis, inflammatory bowel disease, myasthenia gravis, hemophilia, and drug reversal. (See 'Indications' above.)

●Administration – Pay attention to the dose, route, and potential drug interactions. In certain conditions, patients may receive >1 mAb. If plasmapheresis is used, the timing should minimize removal of the mAb. (See 'Administration' above.)

●Adverse effects – Adverse effects of mAbs include infusion reactions, cytokine release syndrome, immune-related effects, infections, autoimmunity, off-target effects, and interference with certain laboratory tests such as pretransfusion 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. (See 'Resistance' above.)

●IVIG and SCIG – Separate topics discuss polyclonal antibody preparations including subcutaneous and intravenous immune globulin (SCIG and IVIG). (See "Subcutaneous and intramuscular immune globulin therapy" and "Immune globulin therapy in inborn errors of immunity" 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 earlier versions of this topic review.