Biological Response Modifier - an overview (2023)

Immune-Mediated Neutropenia

Immune-mediated neutropenia is usually associated with the presence of circulating antineutrophil antibodies, which may mediate neutrophil destruction by complement-mediated lysis or splenic phagocytosis of opsonized neutrophils, or by accelerated apoptosis of mature neutrophils or myeloid precursors.

Alloimmune neonatal neutropenia occurs after transplacental transfer of maternal alloantibodies directed against antigens on the infant's neutrophils, analogous to Rh-hemolytic disease. Prenatal sensitization induces maternal IgG antibodies to neutrophil antigens on fetal cells. The neutropenia is often severe and infants may present within the 1st 2 wk of life with skin or umbilical infections, fever, and pneumonia caused by the usual microbes that cause neonatal disease. By 7 wk of age, the neutrophil count usually returns to normal, reflecting the decay of maternal antibodies in the infant's circulation. Treatment consists of supportive care and appropriate antibiotics for clinical infections, plus granulocyte colony-stimulating factor (G-CSF) for severe infections without neutrophil recovery.

Mothers with autoimmune disease may give birth to infants who develop transient neutropenia, known asneonatal passive autoimmune neutropenia. The duration of the neutropenia depends on the time required for the infant to clear the maternally transferred circulating IgG antibody. It persists in most cases for a few weeks to a few months. Neonates almost always remain asymptomatic.

Autoimmune neutropenia (AIN) of infancy is a benign condition with an annual incidence of approximately 1 per 100,000 among children between infancy and 10 yr of age. Patients usually have severe neutropenia on presentation, with ANC <500/µL, but the total WBC count is generally within normal limits. Monocytosis or eosinophilia may occur but does not impact the low rate of infection. The median age of presentation is 8-11 mo, with a range of 2-54 mo. The diagnosis is often evident when a blood count incidentally reveals neutropenia in a child with a minor infection or when a routine complete blood count is obtained at the 12 mo well-child visit. Occasionally, children may present with more severe infections, including abscesses, pneumonia, or sepsis. The diagnosis may be supported by the presence of antineutrophil antibodies in serum; however, the test has frequent false-negative and false-positive results, so the absence of detectable antineutrophil antibodies does not exclude the diagnosis, and a positive result does not exclude other conditions. Therefore the diagnosis is best made clinically based on a benign course and, if obtained, a normal or hyperplastic myeloid maturation in the bone marrow. There is considerable overlap between AIN of infancy and “chronic benign neutropenia.”

Treatment is not generally necessary because the disease is only rarely associated with severe infection and usually remits spontaneously. Low-dose G-CSF may be useful for severe infections, to promote wound healing following surgery, or to avert emergency room visits or hospitalizations for febrile illnesses. Longitudinal studies of infants with AIN demonstrate median duration of disease ranging from 7-30 mo. Affected children generally have no evidence or risk of other autoimmune diseases.

Biological Response Modifiers

BRMs direct the myriad complex interactions of the immune system. BRMs include erythropoietins, interferons, interleukins, colony-stimulating factors, granulocyte and macrophage colony-stimulating factors, stem cell growth factors, monoclonal antibodies, tumor necrosis factor inhibitors, and vaccines.²⁸A growing understanding of the structure and function of BRMs is driving the discovery and creation of many novel compounds including synthetic analgesics, antioxidants, and antiviral and antibacterial substances. For example, BRMs are being used to treat debilitating rheumatoid arthritis by targeting cytokines that contribute to the disease process.²⁹ By neutralizing or eliminating these targeted cytokines, BRMs may reduce symptoms and decrease inflammation. BRMs may also be used as anticarcinogens, with the following goals: (1) to stop, control, or suppress processes that permit cancer growth; (2) to make cancer cells more recognizable, and therefore more susceptible, to destruction by the immune system; (3) to boost the killing power of immune system cells, such as T cells, natural killer cells, and macrophages; (4) to alter growth patterns in cancer cells to promote behavior like that of healthy cells; (5) to block or reverse the processes that change a normal cell or a precancerous cell into a cancerous cell; (6) to enhance the ability of the body to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation; and (7) to prevent cancer cells from spreading to other parts of the body.^30,31

More of these promising new drugs are currently in development. It can be readily theorized that research to develop various BRMs can be subverted to a malicious end. That is, instead of using BRMs to suppress cancer growth or to decrease disease susceptibility, researchers could develop compounds to cause illness and death. Other drugs could be designed to alter certain metabolic processes or to alter brain chemistry to affect cognition or mood. The opportunity for mischief is limited only by the imagination of the person with ill intent.

Immune-Mediated Neuropathies

The immune-mediated neuropathies are a large and heterogeneous group of diseases. We shall focus on acute inflammatory demyelinating polyneuropathy (AIDP) and chronic inflammatory demyelinating polyneuropathy (CIDP), which may be defined by the time to peak disability; in the former, 4 weeks, and in the latter, 2 months. Although AIDP and CIDP share many characteristics, the question of whether one is a continuum of the other is still under debate. AIDP or Guillain-Barré syndrome (GBS) usually presents with symmetrical ascending weakness and may be associated with autonomic dysfunction and respiratory depression. Sensory systems may be involved and may present with paresthesias or numbness. Demyelination and axonal damage may be involved to varying degrees. If the patient’s symptoms continue to progress beyond 4 weeks, the illness is termedCIDP.

AIDP is the most common acute paralytic disease in the Western world, with a mean annual incidence of 1.8 per 100,000 persons. There is an increasing incidence with age. Mortality was generally due to respiratory failure and has now been significantly reduced with the introduction of positive-pressure ventilation. Epidemics have been found, most notably in northern China, where a high incidence has been associated withC. jejuni infections (McKhann, etal., 1993).

AIDP or GBS is characterized pathologically by an endoneurial lymphocytic, monocytic, and macrophage infiltrate. Several autoantibodies to myelin glycolipids have been identified; including GM1, GD1a, and GD1b. Antibody-mediated demyelination due to complement fixation has been identified in pathology specimens. In some cases, axonal damage is present and is believed to be a result of bystander damage. Activation of calcium-dependent processes within the nerve, including calpain activation, has been shown in animal models to augment axonal degeneration (O’Hanlon etal., 2003). GBS is primarily an antibody-mediated disease, as evidenced by the fact that many patients improve after treatment with plasmapheresis, and that serum from GBS patients causes demyelination after transfer into experimental animals and peripheral nerve cultures. The Miller-Fisher variant of GBS is characterized by ophthalmoplegia, ataxia, and areflexia and is associated with the presence of GQ1b antibodies in the serum.

The occurrence of AIDP has been linked to many infectious diseases, includingC. jejuni, herpesvirus,Mycoplasma pneumoniae, and many other bacterial and viral infections, as well as vaccinations. The incidence of infection has been reported to be 90% in the 30 days before occurrence of GBS.C. jejuni is one of the most commonly identifiable agents, and molecular mimicry and host susceptibility play a role in disease pathogenesis. Autoantibodies not present in controls have been identified in the sera of GBS patients associated withC. jejuni, including autoantibodies to the gangliosides GM1, GD1a, GD1b, and GQ1b (Sheikh, etal., 1998).

1 Introduction

Biologic response modifiers (BRMs) are endogenous (ie, naturally produced in the body) or exogenous (administered together with a drug) agents that modulate immunity. BRMs regulate, among others, the type, duration, and intensity of immune responses and are characterized by pleiotropy and redundancy. The thymic polypeptide prothymosin alpha (proTα) has been incorporated in the large family of BRMs, mainly because of its modulating effects on several properties of immune effectors. Its wide distribution in cells, tissues, and organs, its broad phylogenetic dissemination and the lack of a mechanism supporting its secretion, questioned the initial characterization of proTα as “thymic hormone.” Now, it is widely acknowledged that proTα possesses an essential intracellular role related to cell survival and growth, and at the same time, extracellularly it enhances the functionalities of diverse subpopulations of the immune system. Several novel functions, beyond immunomodulation, have also been ascribed to proTα.

Accumulated data suggest that its immunopotentiating activity could be therapeutically exploited in various clinical conditions associated with immunodeficiency, immunosenescence, cancer, and autoimmune diseases. Herein, we present the most prominent effects of the polypeptide, as reported by various research teams for over 30 years, propose a compiled scenario on its mode of action, and provide means, which eventually could lead to its incorporation in clinical trials as an immunostimulant/adjuvant.

Immune-Mediated Mechanisms

HCV infection elicits an immune response in the host that involves both an initial innate response and a subsequent adaptive response. The innate response is the first line of defense against the virus and includes several arms such as natural killer (NK) cell activation and cellular antiviral mechanisms triggered by pathogen-associated molecular patterns recognized by the cell (seeChapter 2). These processes can lead to apoptosis of infected cells within the first few hours of infection. NK cells, as the effector cells of the innate immune system, also produce TNF-β and IFN-α, cytokines that are critical for dendritic cell maturation and subsequent induction of adaptive immunity. NK cells can also attack virus-infected cells directly, as do other immune cells by different effector molecules.¹⁰⁸ Subsequently, however, the virus initiates a number of mechanisms that undermine the ability of the host to control the infection.

Virus-related disruption of the innate, and later adaptive, immune response occurs at several levels. NK cell function is slowed possibly because NK cell-mediated cytotoxicity and production of cytokines are interrupted when the HCV E2 protein binds its cellular receptor CD81.¹⁰⁹ Expression of TNF-related apoptosis-inducing ligand on NK cells correlates with disease activity in both acute¹¹⁰ and chronic¹¹¹ hepatitis C, thereby suggesting that NK cells have a direct role in the immunopathogenesis of hepatitis C. Pathogen-associated molecular patterns activate several cellular processes, including the JAK-STAT (Janus kinase‒signal transducer and activator of transcription) proteins pathway and Toll-like receptor-3, activation of both of which ultimately results in production of cellular IFNs, IFN-stimulated genes (ISGs), and IFN-regulated factors that convey antiviral properties to the cell. NS3/4 protease degrades TRIF, an essential intermediate in this pathway, and cleaves IFN promoter stimulator-1, an intermediate in the signaling cascade, to block activation of IFN when retinoic inducible gene-1 binds viral intermediates.¹¹² In addition, HCV core protein promotes STAT-1 degradation, inhibits STAT-1 phosphorylation, promotes suppressor of cytokine signaling induction (an inhibitor of JAK-STAT signaling), and impairs ISG factor-3 (ISGF3), a heterotrimer of STAT-1, STAT-2, and IFN-β promoter stimulator (IRF-9) from binding to the promoter regions of IFN-stimulated response elements, thereby inhibiting transcription of IFN response genes. Even when IFN response genes are activated, NS5A and E2 both can disrupt protein kinase R function to suppress translation, thereby allowing viral replication to continue.¹¹² In addition, NS5A inhibits 2′-5′-oligoadenylate synthetase, which is expressed in response to HCV infection and leads to HCV RNA degradation. Taken together, HCV is able to disrupt the innate immune response at several levels, and these strategies appear to be pivotal in establishing the chronicity of infection.

Biological response modifiers (BRMs) are natural proteins that alter immune responses and that have been developed as both immunosuppressive and immunostimulating drugs. These may include natural products such as β-glucans or biotherapeutics such as monoclonal antibodies. Immunotoxicity testing of these immune modulators is not currently regulated by International Conference on Harmonization (ICH) guidelines and many of the standard immunotoxicity tests are used for understanding the pharmacology of the molecule. Since many biotherapeutics are only cross-reactive in nonhuman primates (NHPs), the standard immunotoxicity tests may need to be adapted (since rodents are the standard species used for immunotoxicity testing of small-molecule therapeutics). Unanticipated effects on the immune system may or may not be related to the mechanism of action, but would then be considered as immunotoxicity. Immunogenicity must also be assessed, which is the immune response to the drug. All of these factors make immunotoxicity testing of BRMs a challenge to toxicologists working in this field.

Biologic Response Modifiers

BRMs direct the myriad complex interactions of the immune system. BRMs include erythropoietins, interferons, interleukins, colony-stimulating factors, granulocyte and macrophage colony-stimulating factors, stem-cell growth factors, monoclonal antibodies, tumor-necrosis-factor inhibitors, and vaccines.²⁴

A growing understanding of the structure and function of BRMs is driving the discovery and creation of many novel compounds including synthetic analgesics, antioxidants, and antiviral and antibacterial substances. For example, BRMs are being used to treat debilitating rheumatoid arthritis by targeting cytokines that contribute to the disease process.²⁵ By neutralizing or eliminating these targeted cytokines, BRMs may reduce symptoms and decrease inflammation. BRMs may also be used as anticarcinogens, with the following goals: (1) to stop, control, or suppress processes that permit cancer growth, (2) to make cancer cells more recognizable, and therefore more susceptible, to destruction by the immune system, (3) to boost the killing power of immune system cells, such as T cells, natural killer cells, and macrophages, (4) to alter growth patterns in cancer cells to promote behavior like that of healthy cells, (5) to block or reverse the processes that change a normal cell or a precancerous cell into a cancerous cell, (6) to enhance the ability of the body to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation, and (7) to prevent cancer cells from spreading to other parts of the body.^26,27

More of these promising new drugs are currently in development. It can be readily theorized that research to develop various BRMs can be subverted to a malicious end. That is, instead of using BRMs to suppress cancer growth or to decrease disease susceptibility, researchers could develop compounds to cause illness and death. Other drugs could be designed to alter certain metabolic processes or to alter brain chemistry to affect cognition or mood. The opportunity for mischief is limited only by the imagination of the person with ill intent.

Biologics (Biological Response Modifiers)

(Appendix 19.3; see also Chapter 35.)

Biological response modifiers (BRMs) block the inflammatory and immune responses, acting on immunocytes directly or via cytokines, inhibiting cellular activation and inflammatory gene transcription by various means.

Some are antibodies, soluble receptors or natural antagonists; others are small molecules that specifically inhibit intracellular, cell–cell and cell–matrix interactions intrinsic to inflammatory and immune processes. Examples are shown in Appendices 19.3 and 19.4.

TNFα inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab, natalizumab) bind and⁄or neutralize soluble (both circulating and within tissue) and membrane-bound TNFα, so blocking its effects upon target inflammatory cells.

T-cell modulators act on specific CD antigens. Alefacept targets CD2+on memory T and NK cells. B-cell modulators, such as rituximab, act by targeting CD20, selectively depleting circulating B cells. An anti-CD28 is also available (abatacept).

Interleukin inhibitors include an IL-1 antagonist (anakinra) and an IL-6 antagonist (tocilizumab).

Labelled indications for use of BRMs include rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn disease, ulcerative colitis and malignancies such as non-Hodgkin lymphoma. Off-label applications include pemphigus, recurrent aphthous stomatitis and Behçet disease, mucous membrane pemphigoid, lichen planus, orofacial granulomatosis and Sjögren syndrome.

One of the advantages of BRMs is that they act specifically to neutralize targeted immune components so there should, in theory, be relatively few adverse effects. They are administered by injection or infusion, and the most common adverse effect is a mild skin reaction at the injection site. All are injected preparations, with schedules varying with the condition being treated. Infliximab and rituximab must be given as periodic intravenous infusions; etanercept and adalimumab are given as regular subcutaneous injections; and alefacept is given as weekly intramuscular injections. Some patients develop headaches during infusion, and there may be an increased susceptibility to infection – a serious risk to patients already prone to infection (e.g. diabetics) or who have an active infection such as tuberculosis or hepatitis B virus (Tables 19.7 and 19.8). Immunomodulatory mAbs have an inherent risk for adverse immune-mediated drug reactions in humans, such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. Other long-term effects are not yet clear (see also Chs 29 and 35). At least 30 therapeutic mAbs are marketed in a variety of indications, and have already had profound impacts on fields such as oncology, rheumatology, neurology, cardiology and gastroenterology. However, biologics can have a high cost and significant adverse effects, and the efficacy of murine human mAbs can be limited by development of human antichimeric antibodies.

Biologics suppress the immune system and carry an increased risk of infections, which, in rare cases, can be serious. These agents undoubtedly can have serious potential adverse effects but they are generally considered safe. People with tuberculosis, heart failure or multiple sclerosis should not take biologics because they can bring on these conditions or make them worse. In rare cases, some people taking TNF inhibitors have developed certain cancers such as lymphoma. Natalimumab increases the risk of a rare, potentially fatal brain infection – progressive multifocal leukoencephalopathy (PML). Common side-effects from biologic use include headache, ’flu-like symptoms, nausea, rash, injection site pain and infusion reactions.

Use of biologics does require precautionary considerations, including screening for coexisting medical conditions. Before prescribing biologics, it is crucial to check for potential problems, such as active liver infection or tuberculosis. Monitoring includes include laboratory tests and possibly regular checks for cancer (Box 19.3).

Screening for, and use in, comorbid conditions are described below.

Drug Class:

Biologic response modifier

Drug Class:

Antineoplastic