Passive antibody therapy

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Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies (same as immunoglobin) to target and kill pathogens or cancer cells. [1] It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

Contents

History

The timeline of the development of passive antibody therapy. The prevalence roused in the early 1900s and withdrew in the 1930s. It was revived in 1975 and became common cancer therapeutic. Passive antibody therapy timeline (1890-2020).png
The timeline of the development of passive antibody therapy. The prevalence roused in the early 1900s and withdrew in the 1930s. It was revived in 1975 and became common cancer therapeutic.

Passive antibody therapy was first propounded by Emil von Behring and Shibasaburo Kitasato in 1890 to treat diphtheria after the observation of immunization in rabbits after injecting serum from tetanus-immunized rabbits. Later in 1891, Paul Ehrlich joined Behring's and Kitasato's research to ameliorate immunizability from lethal toxins. This established the basis of antibody immunotherapy. With the ideology of using antibody serum to treat infectious diseases, the three scientists standardized serum production in dairy cows and merchandised serum vaccines for tetanus and diphtheria.

The prevalence of serum therapy surged in the early 19th century. When the H1N1 influenza pandemic (Spanish flu) struck the US and Europe, serum containing antibodies from recovered patients are prevalently injected into patients. With proven therapeutic effects, the applications expanded to other viral and bacterial infections, such as pneumococcus, meningococcus, and rabies, despite an unknown underlying mechanism. Yet, severe anaphylactic reactions and hypersensitivity were common, ergo, serum therapy was pulled out from the market in the 1940s. The resurrection of antibody immunotherapy contributed to Cesar Milstein and Georges J. F. Kohler, who manifested the mass production of pure monoclonal antibodies with limited adverse effects in 1975. Since then, passive antibody therapy has become prevailed as cancer therapeutics and viral treatments.

Classification of passive immunity therapy

Monoclonal Antibodies (mAb)Polyclonal Antibodies (pAb)
CharacteristicsA single type of antibodies that recognize one epitope of an antigenContain a mixture of antibodies that can recognize multiple epitopes on a single type of antigen
Manufacture processCreate hybridoma: isolate B lymphocytes from animal spleen and fuse with myeloma cell lineDirectly collect serum from immunized animals and purify the solution to remove other serum proteins
Advantages- high homogeneity (low batch-to-batch variability)

- high specificity and low cross-reactivity

- high sensitivity

- inexpensive to produce

- high overall affinity

- bind to target antigen quicker

Disadvantages- expensive to produce

- long production time

- overall affinity is lower than polyclonal antibodies

- high batch-to-batch variability

- low specificity and high cross-reactivity

Monoclonal antibodies (mAb)

A general representation of the production of monoclonal antibodies. Monoclonal antibodies smaller.jpg
A general representation of the production of monoclonal antibodies.

Monoclonal antibodies are manufactured ex vivo from a single B lymphocyte. Serum from immunized animals or humans is first extracted and purified to collect B lymphocytes from the spleen, which are then fused with plasma cell myeloma. After culturing the fused myeloma cell lines, the colonies are selected with the antigens: positive colonies with suitable antibodies can bind to the epitope of the antigen and kill pathogens, whereas colonies without targeted antibodies are eliminated. [2] Upon injection, these homogenous antibodies produced from a single B cell can target a specific epitope on the antigen. [3] The major advantage of using monoclonal antibodies is their specific action towards the target since it only contains one antibody binding site per se, it minimizes cross-reactivity (the activity that antibodies unintentionally bind to non-targeted antigens). [4] However, monoclonal antibodies also mean that overall affinity is lower owing to the limited ability to recognize different epitopes on the antigens, which may lead to incomplete elimination of pathogens and tumor cells. The production time and cost is high as well, limiting its generalizability and prevalence of usage. [5]

Polyclonal antibodies (pAb)

The process of manufacturing polyclonal antibodies is similar to that of monoclonal antibodies, which begins with inoculation of antigen conjugate into suitable animals, except multiple B lymphocytes are collected and cultured instead of a single B lymphocyte. [6] Production of polyclonal antibodies circumvents the procedure of ex vivo fabrication of hybridoma cell line and requires minimal purification. The manufacturing cost and time are wherefore reduced. Due to a heterogeneous origin, the antibodies express various subtypes of immunoglobulin against the antigen [3] which has an overall higher affinity and can better detect low-quantity antigens by targeting different epitopes on the antigen. [7] However, it also provokes an increased chance of non-specific reactivity because the antibodies might bind to non-diseases causing substances. In addition, as serum batch may contain various antibodies at different concentrations, it is laborious to corroborate the constituents of every batch.

Mechanism of Action

Since some patients fail to produce antibodies effectively and hence have poorer immune responses, passive antibody therapy can reinforce their immune system through the introduction of antibodies from donors. Antibodies are glycoproteins that are naturally produced by the immune system. Each antibody contains four polypeptides of Y shapes and has unique recognition sites of the targets, such as cell surface antigen, and transmembrane proteins on cancer cells and infectious organisms (viruses and bacteria). Upon binding to the antigen, antibodies trigger different cascades to neutralize toxins and kill the cells. There are three ways of action: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

Antagonistic reaction (Neutralization) and Agonistic reaction

Antagonism by antibodies eliminates antigens by binding to the relevant Fc receptors or pathogens for disrupting the toxins from binding to the receptors. In cancers, tumor cells escape immune vigilance by binding to checkpoint proteins on immune cells for inhibiting immune signaling and downregulating the expression of major histocompatibility class I (MHC I). [8] Antagonistic antibodies, also called immune checkpoints inhibitors, obstruct the binding between cancer cells and immune checkpoints to antagonize cancer cells’ action and restore immune surveillance. Therefore, immune cells can recognize the surface antigens on the tumor cells to elicit immune responses. Examples of drugs that exploit such a mechanism include pembrolizumab and telimomab.

Apart from directing the inhibitory pathways, agonistic antibodies can target immunostimulatory receptors to elicit immune responses. Upon binding between cluster of differentiation proteins (CD proteins) and agonistic antibodies, antigen-presenting cells, such as dendritic cells, B lymphocytes and monocytes, are stimulated to secrete proinflammatory cytokines to remove pathogens and malignant cells. For example, the ligation of CD40 monoclonal antibodies and CD40 on tumor cells license antigen-presenting cells (predominantly dendritic cells) to increase the presentation of tumor-associated antigens (TAA) to local cytotoxic T lymphocytes to kill tumor cells. [8]

Illustration of complement cascade 2212 Complement Cascade and Function.jpg
Illustration of complement cascade

Complement-dependent Cytotoxicity (CDC) Pathway

Antibodies can also trigger the classical pathway – one of the three pathways of the complement cascade. Briefly, the C1 protein attaches to the pathogen surface and the antibody-antigen complex that culminates in the generation of C3 convertase, followed by the cleavage of C3 protein into C3a and C3b protein. C3a protein serves as an inflammation mediator to recruit phagocytes. On the other hand, C3 protein can opsonize pathogens and bind to C3 convertase to catalyze the formation of C5 convertase to produce C5a and C5b for terminal complement components assembly. [9] The formation of complement proteins (C3a, C3b, C5a, C5b, etc.) ultimately congregates into a membrane-attack complex to lyse the membrane of pathogens. [10]

In addition to the generation of complement proteins, C1 complex also induces the activation of B cells, monocytes, macrophages, and neutrophils to trigger immune responses, for instance, vasodilation and increased vascular permeability at the infection site.

Antibody-dependent Cellular Cytotoxicity (ADCC) Pathway

Several monoclonal antibody drugs such as Rituximab manipulate the ADCC pathway to eradicate cancer cells. Firstly, the Fab region of the antibodies (tip of the Y-shaped-antibody) first binds to the epitope of the pathogens or the immunoreceptors of cancer cells; whereas the Fc region (stem of the antibody) binds to natural killer cells to phosphorylate the immunoreceptor. Several notable immunoreceptors for cancer treatment include epidermal growth factor receptor (EFGR), insulin-like growth factor receptor (IGFR), and cMET as they are commonly overexpressed in malignant cells. Phosphorylation of immunoreceptors triggers the release of cytotoxic granules from the natural killer cells which sequentially perturbs cell-cell signaling via the induction of the apoptotic cascade (Bax, Bad, etc.), [11] leading to cell death and enhancing the susceptibility of cancer cells to chemotherapy or radiotherapy.

Application on Cancer

The structure of monoclonal antibodies. Mouse (top-left, o), chimeric (top-right, xi), humanized (bottom-left, zu), and fully human(bottom right, u) antibodies. Human parts are shown in brown, and murine parts in blue. Chimeric and humanized antibodies.svg
The structure of monoclonal antibodies. Mouse (top-left, o), chimeric (top-right, xi), humanized (bottom-left, zu), and fully human(bottom right, u) antibodies. Human parts are shown in brown, and murine parts in blue.
Rituximab binds to CD20 on a B Cell Surface. Rituxima Binding to CD20 on a B Cell Surface (6830897205).jpg
Rituximab binds to CD20 on a B Cell Surface.
Brentuximab Vedotin is an antibody-drug conjugate. Antibody-drug conjugate structure.svg
Brentuximab Vedotin is an antibody-drug conjugate.

Passive antibody administration has become a widely approved cancer treatment following the development of monoclonal antibody (mAb). Since these antibodies originated from mice, they were wrought with problems of immunogenetics and poor abilities to induce an immune response in the human body, limiting their clinical applicability. [12] Later development of antibody engineering enabled the production of chimeric antibodies (antibodies with human Fc region and mouse Fab region), humanized antibodies (antibodies with replaced mouse complementarity-determining regions and human backbone), and full human antibodies (antibodies produced by transgenic mice), which satisfactorily addressed many of these problems and were suitable for the clinical cancer treatment. [13]

Cetuximab

Cetuximab (trade name: Erbitux ) is a recombinant chimeric monoclonal antibody designed to treat metastatic colorectal cancer and head and neck cancer. [14] In numerous cancers, the epidermal growth factor receptor (EGFR) is often inappropriately activated and overexpressed in cancer cells, leading to uncontrolled cell growth. [15] Cetuximab blocks ligand binding of EGFR and inhibits intracellular downstream events critical for tumor survival, thereby inducing tumor regression by reducing cell proliferation and increasing apoptosis. [15] It is administered by intravenous injection and is often prescribed in combination with radiotherapy or other chemotherapeutic regimens such as irinotecan. Since EGFR plays an essential role in maintaining skin integrity, one serious side effect of Cetuximab therapy is skin problems such as acne-like rash, skin drying and cracking due to the inhibition of EGFR. [14] Other serious side effects are severe allergic reactions and heart attacks. [16]

Rituximab

In 1997, the FDA approved rituximab (trade names: Rituxan, MabThera) as the first monoclonal antibody for clinical cancer treatment. [17] This drug directly targets CD20 that is found on the surface of both normal and malignant B cells and is indicated to treat blood cancers, such as non-Hodgkin's lymphoma (a type of B cell lymphoma) and chronic lymphocytic leukemia (B cell malignancy), and other conditions like rheumatoid arthritis and vasculitis. [18] The mechanism of action includes B-cell lysis by antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). [19] Common side effects include itching, headache, nausea, diarrhea and low blood pressure. [20]

Brentuximab vedotin

Brentuximab vedotin (trade name: Adcetris) is a CD30 targeted antibody-drug conjugate (ADC), i.e. a monoclonal antibody chemically linked to a drug, and is constructed by chimeric anit-CD30 IgG1 antibody (cAC10), monomethyl auristatin E (MMAE, a potent cytotoxic drug) and a linker that attaches MMAE covalently to cAC10. [21] The binding of brentuximab vedotin to tumor cells is followed by the release of cytotoxic drug MMAE, which destroys the microtubule network within the cell and induces cell apoptosis. [22] Brentuximab vedotin became the first antibody-drug conjugate approved by FDA to treat Hodgkin's lymphoma and anaplastic large-cell lymphoma in 2011. [23]

Application on infectious diseases

Palivizumab

In 1998, the FDA approved the medical use of palivizumab (trade name: Synagis), which is a humanized monoclonal antibody used as prophylaxis to prevent severe diseases caused by respiratory syncytial virus (RSV) - the leading cause of lower respiratory tract infections in infants. [24] The drug is recommended for infants with a high risk of RSV infection due to prematurity or diseases such as congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). [24] However, it will not treat children already infected with RSV. Injected intramuscularly, it binds to RSV fusion proteins to prevent RSV from binding to host cell receptors and uptake. Common side effects are diarrhea, vomiting, runny nose and other cold symptoms. [25]

An overview of HIV entry. Ibalizumab is used to prevent the binding of HIV to CD4 and thus blocks HIV entry. HIV attachment.gif
An overview of HIV entry. Ibalizumab is used to prevent the binding of HIV to CD4 and thus blocks HIV entry.

Ibalizumab

Ibalizumab (trade name: Trogarzo) is a new antiviral drug specifically for adults with HIV who have tried but developed resistant against other HIV therapies. The entry of HIV into human immune cells requires the binding of the GP120 (an envelope glycoprotein on the surface of HIV) to CD4 (a receptor on the immune cell surface) to induce the structural shift in the GP120. [26] Ibalizumab binds to the CD4 receptor to prevent the post-attachment conformational changes in CD4-HIV envelope GP120 complex and therefore hinders the viral entry into host cells and prevents the HIV-infected cells from infecting other normal cells. [27] The advantages of using Ibalizumab as HIV therapy are low toxicity, good drug resistance, high antiviral effect and synergy with other antiviral drugs. [27]

Perspective and future opportunities

Although passive administration of antibodies was used to treat infectious diseases 100 years ago, there are only a few therapeutic antibodies approved for the clinical treatments of infectious diseases currently. However, there are an increasing number of ongoing research and clinical developments on the applications of monoclonal antibodies in the therapy of viral infections without available vaccines, such as Ebola, MERS, and Zika, and infectious diseases without effective anti-viral drugs such as influenza and rabies. [28] The most recent research focuses on the development of monoclonal antibody therapy for treating COVID-19.

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Monoclonal antibody</span> Antibodies from clones of the same blood cell

A monoclonal antibody is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

CD4 immunoadhesin is a recombinant fusion protein consisting of a combination of CD4 and the fragment crystallizable region, similarly known as immunoglobulin. It belongs to the antibody (Ig) gene family. CD4 is a surface receptor for human immunodeficiency virus (HIV). The CD4 immunoadhesin molecular fusion allow the protein to possess key functions from each independent subunit. The CD4 specific properties include the gp120-binding and HIV-blocking capabilities. Properties specific to immunoglobulin are the long plasma half-life and Fc receptor binding. The properties of the protein means that it has potential to be used in AIDS therapy as of 2017. Specifically, CD4 immunoadhesin plays a role in antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells. While natural anti-gp120 antibodies exhibit a response towards uninfected CD4-expressing cells that have a soluble gp120 bound to the CD4 on the cell surface, CD4 immunoadhesin, however, will not exhibit a response. One of the most relevant of these possibilities is its ability to cross the placenta.

A bispecific monoclonal antibody is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seagen in the US.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited due to the fact that it can cause severe liver toxicity.

References

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  27. 1 2 Iacob, Simona A.; Iacob, Diana G. (27 November 2017). "Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy". Frontiers in Microbiology. 8: 2323. doi: 10.3389/fmicb.2017.02323 . ISSN   1664-302X. PMC   5711820 . PMID   29230203.
  28. ↑ Graham, Barney S.; Ambrosino, Donna M. (May 2015). "History of passive antibody administration for prevention and treatment of infectious diseases". Current Opinion in HIV and AIDS. 10 (3): 129–134. doi:10.1097/COH.0000000000000154. ISSN   1746-630X. PMC   4437582 . PMID   25760933.
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