Monoclonal Antibodies Treatment for Rare & Neglected Diseases PDF

**Table of Content** **Authors: 2** [**Abstract: 2**](%5Cl) [**Keywords: 2**](%5Cl) [**Introduction: 2**](%5Cl) [**Rare Diseases: 3**](%5Cl) [Amyloid transthyretin (TTR) amyloidosis (ATTR amyloidosis): 3](%5Cl) [Homozygous Familial Hypercholesterolemia: 5](%5Cl) [Yellow fever: 6](%5Cl) [Fib...

**Table of Content** **Authors: 2** [**Abstract: 2**](%5Cl) [**Keywords: 2**](%5Cl) [**Introduction: 2**](%5Cl) [**Rare Diseases: 3**](%5Cl) [Amyloid transthyretin (TTR) amyloidosis (ATTR amyloidosis): 3](%5Cl) [Homozygous Familial Hypercholesterolemia: 5](%5Cl) [Yellow fever: 6](%5Cl) [Fibrodysplasia Ossificans Progressiva (FOP): 7](%5Cl) [Giant cell tumor of bone: 8](%5Cl) [Myasthenia Gravis (MG): 9](%5Cl) [Hemophilia: 11](%5Cl) [Acquired  thrombotic thrombocytopenic purpura (aTTP): 13](%5Cl) [**Neglected Tropical Diseases and Rare diseases: 13**](%5Cl) [Ebola Virus Disease: 13](%5Cl) [Western Equine Encephalitis and Venezuelan Equine Encephalitis: 15](%5Cl) [**Neglected Tropical Diseases (NTDs): 16**](%5Cl) [Schistosomiasis( bilharzia): 16](%5Cl) [Human African Trypanosomiasis (HAT): 18](%5Cl) [Malaria: 19](%5Cl) [Systemic Fungal Infections: 21](%5Cl) [Leishmaniasis: 27](%5Cl) [Hapititis B: 28](%5Cl) [Bacterial Infections: 29](%5Cl) [RSV: 30](%5Cl) [Rabies: 31](%5Cl) [HIV: 32](%5Cl) [Dengue: 34](%5Cl) [CHAPEL: 36](%5Cl) [**Animal bites and stings : 36**](%5Cl) [**Challenges for Monoclonal Antibodies development: 37**](%5Cl) [**Cost effectiveness of Monoclonal Antibody Therapies: 38**](%5Cl) [**Future Perspectives: 39**](%5Cl) A landscape view of Monoclonal Antibodies (mAbs) use in treatment of rare and Neglected Tropical Diseases (NTD), challenges, cost effectiveness and future directions. Authors: ======== Abstract: ========= Rare and neglected tropical diseases (NTDs) are often overlooked due to limited awareness, scientific understanding, and funding, especially NTDs despite their significant burden on underserved populations in low-income regions of the world. Existing treatments are insufficient, leaving millions without effective therapy. This review highlights the transformative potential of monoclonal antibodies (mAbs) as a precise and targeted approach paving the way for innovations to address unmet clinical needs of rare diseases (e.g., ATTR amyloidosis, HoFH, etc.) and NTDs (e.g., malaria, schistosomiasis, Ebola, etc.) by improving therapeutic efficacy, reducing disease burden, and improving diagnostics. However, their therapeutic application is constrained by high production costs, limited accessibility, and underdeveloped research infrastructure. By evaluating existing monoclonal antibodies (mAbs), identifying promising targets, and exploring combination therapies, it advoctes to revolutionize treatment by the broader adoption of mAbs-based therapies to bridge healthcare gaps for NTDs and rare diseases and promote their equitable access advancing global health outcomes. Keywords: ========= Monoclonal antibodies, rare diseases, neglected diseases, neglected tropical diseases Introduction: ============= Monoclonal antibodies (mAbs) are highly specific laboratory-made antibodies generated from the same B lymphocyte clones that are engineered to recognize and bind to specific antigens with high precision. Since mAbs are derived from the same clone, they are uniform in their structure, antigen-binding site, and biological functions, unlike polyclonal antibodies, which recognize and bind to multiple epitopes on an antigen. In 1975, César Milstein and Georges Köhler produced the first murine mAb using hyridoma technology by fusing human B cells with mouse spleen cells, enabling the mass production of identical monoclonal antibodies. There are four types of mAb. First one is murine mAbs, derived entirely from mouse immune systems but often induce high immunogenicity in humans, leading to allergic reactions or human anti-mouse antibody (HAMA) responses.For instance, OKT-3 was first used to treat transplant rejection. The second kind of mAbs are chimeric ones, which are created by fusing human constant regions (\~65% human) with murine variable regions. Their immunogenicity is lower than that of murine antibodies. Rituximab and Infliximab are two examples. Humanized mAbs are the third type; they are composed of around \~95% human sequences with hypervariable sections from mice grafted onto human frames. Although they may have a lower binding affinity, they exhibit improved compatibility for human use. Alemtuzumab and Daclizumab are two examples. Fully human mAbs are the most advanced kind and are made with the use of technology such as phage display platforms and transgenic mice. They minimize immunological reactions since they are wholly human sequences. Adalimumab and Panitumumab are two examples. Due to their remarkable specificity, binding strength and targeted action, mAbs have become invaluable in medical and diagnostic fields. They are versatile therapeutics used in cancer treatment to deliver targeted medicines, cause cytotoxicity, or stop tumor growth (e.g., Trastuzumab, Bevacizumab). They treat infectious disorders by neutralizing pathogens or important proteins (e.g., anti-HIV mAbs) and autoimmune diseases by decreasing T-cells or inflammatory cytokines (e.g., Infliximab, Omalizumab). Evolocumab and Alirocumab are examples of mAbs that control glucose and lipid metabolism in metabolic diseases. Basiliximab, on the other hand, suppresses immune responses to prevent graft rejection in organ transplantation. Furthermore, mAbs are essential components of immunodiagnostic testing, helping to accurately identify infectious organisms, antigens, and antibodies. (ajol) (Introduction on Monoclonal Antibodies) Rare, and Neglected Tropical Diseases (NTD) are the hidden patterns in the fabric of our life, veiled by the shadow of ignorance, awaiting discovery. Rare diseases are the diseases that impact small percentage of population and Neglected Tropical Diseases (NTD) are the tropical infections common in low-income and tropical, sub-tropical countries. Rare diseases affects 10% of the population. The drugs that are used to treat the rare diseases are called as orphan drugs. Some diseases are rare in some parts of the world while not in other parts of the world. According to the US Orphan Drug Act 1983, a disease is considered rare when it affects less than 200,000 people and according to European Union a disease is a rare disease when it affects 1in 2000 people (how many rare diseases are there?). NTD are considered neglected when they lack drugs that are effective, infect people who lack access to treatments and is common in poorest countries.(the worlds most neglected diseases). Conventional treatments lack the effectiveness in treating rare and NTDs, most of the diseases don't have much scientific understanding as a result symptoms are often overlooked or confused with some other conditions. Many vaccines and drugs available have been shown to be effective in animal models but their effectiveness in humans is yet to be well studied. In the admist of all these Monoclonal Antibodies( mAbs) provide a novel approach in diagnosing and treating these diseases. In the light of this challenge this review discusses the rare and neglected tropical diseases like shistosomiasis, ebola virus, western equine and venezuelan equine encephalitis, malaria, hepatitis B, Zika virus disease, fibrodysplasia ossificans progressiva(FOP), fungal infections, amyloid transthyretin amylodiosis, hepatitis C etc and their conventinal treatment, their challenges, mAbs with potential to diagnose or treat these diseases.The main challenge in adaption of mAbs is the high cost, the review also evaluates cost effectiveness and discusses future directions that can be helpful to combat these diseases that hide in the plain sight. This research aims to promotes dialogue among researchers, policymakers, and pharmaceutical companies, encouraging investment and collaboration to bring these treatments to the forefront of global healthcare. Rare Diseases: ============== Amyloid transthyretin (TTR) amyloidosis (ATTR amyloidosis): ----------------------------------------------------------- Misfolding of Transthyretin (TTR), which is a 127-amino acid, 56-kDa prealbumin transport protein, either because of genetic mutations or aging, causes Amyloid transthyretin amyloidosis (ATTR) also referred as Transthyretin amyloidosis and Transthyretin cardiac amyloidosis (ATTR-CA). ATTR amyloidosis is a life-threatening disorder charcterized by extracellular deposition of amyloid fibrils (caused by dissociation TTR tetramers and its monomers' misassembly) composed of misfolded transthyretin (TTR). There exist two types of TTR Amyloidosis. First is Wild-Type TTR or ATTRwt (Senile Systemic Amyloidosis, SSA), that is sporadic, age-related disease caused by misassembly of wild-type TTR. Second one is Variant TTR or ATTRv (Familial Transthyretin Amyloidosis), caused by misfolding of a genetically mutated TTR and presents as familial amyloid cardiomyopathy or familial amyloidotic polyneuropathy (FAP).*(Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments)(Transthyretin (TTR) Cardiac Amyloidosis).*Both AATRwt and ATTRv amyloidosis ( affects 5,000--10,000 people globally) are rare diseases, but the prevalence of ATTRwt amyloidosis is underestimated.(Amyloidosis---the Diagnosis and Treatment of an Underdiagnosed Disease). Misdiagnosis is one of its challenge faced by its patients despite advancements in genetic, biochemical, and immunohistochemical diagnostics. Tafamidis was the first approved treatment, that prevent amyloid fibril formation by stablizing TTR protein. Other therapies include acoramidis, gene-editing therapies and gene-silencing agents, aim to reduce misfolded TTR production or remove amyloid fibrils. *(Evolution of Disease-modifying Therapy for Transthyretin Cardiac Amyloidosis)(Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-*modifying treatments)(Transthyretin (TTR) Cardiac Amyloidosis) One of the emerging therapeutic approach for treating ATTR, particularly its cardiac form (ATTR-CM), is monoclonal antibodies. Several monoclonal antibodies are being tested in clinical trials to inhibit the formation of amyloid fibrils that deposit in various organs. (Development of orphan drugs for rare disease).One of these monoclonal antibody targets Serum Amyloid P component (SAP) which is present in amyloid fibrils. This mAb works synergistically with CPHPC that diminishes SAP from the plasma, however, leaving some of it in amyloid deposits, anti-SAP antibodies then targets them to promote amyloid clearance. It has shown safety in phase 1 clinical trial in reducing amyloid fibrils in the, kidneys, liver and lymph nodes. (Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component) (Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges) Another mAb, ALXN-2220, lowers cardiac biomarkers and amyloid load markers thus reducing cardiac amyloid TTR deposits. It has shown long-term safety, efficacy and no severe adverse events in clinical trials, with continued benefits beyond 12 months. (Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101). Continued researches led to the identification of four other monoclonal antibodies that selectively target exposed epitopes on misfolded, non-native TTR forms, without binding to other amyloid types or normal tissue.. They promote phagocytic uptake by macrophage cells, and targeted amyloid-positive TTR deposits in cardiac tissues. Thus they inhibit TTR fibril in vitro. (Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin)(Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care) Ongoing research is focused on optimizing dosing regimens and exploring combination therapies with already present treatments like tafamidis(Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis).This proves that monoclonal antibodies has the potential to reverse disease progression in advanced cases of ATTR-CM. (Evolution of Disease-modifying Therapy for Transthyretin Cardiac Amyloidosis). Homozygous Familial Hypercholesterolemia: ----------------------------------------- Familial hypercholesterolemia (FH) is a hereditary condition that causes people to have significantly higher levels of low-density lipoprotein (LDL) cholesterol (LDL-C), sometimes known as \"bad cholesterol.\" If left untreated, this condition increases the chance of developing coronary artery disease early.Mutations in the LDLR, APOB, and PCSK9 genes are the reason. While homozygous FH, or HoFH, is a rarer variety (1 in 250,000), it contains mutations in both gene copies. Heterozygous FH, or HeFH, is more prevalent, involving one mutated gene copy from each parent. Adolescents with HoFH frequently develop serious vascular conditions like CAD and aortic stenosis, which can cause death by the age of thirty. Statins and ezetimibe are traditional trratments but HoFH patients have poor response to standard therapy like statins, which are unsuccessful for most. For HoFH, monoclonal antibodies that target PCSK9 and ANGPTL3 have shown promise, particularly in individuals who are statin intolerant or who don\'t respond well to conventional therapy. These medications lessen the cardiovascular risk linked to this hereditary condition by lowering LDL-C levels. HoFh patients with residual LDLR activity have shown efficacy from monoclonal anti-PCSK9 antibodies (evolocumab and alirocumab) providing an average LDL-C reduction of 24% (Homozygous familial hypercholesterolemia: what treatments are on the horizon?) but often fail to lower LDL cholesterol to optimal levels, despite their effectiveness in other patient groups (PCSK9 inhibitors: monoclonal antibodies for the treatment of hypercholesterolemia.)., while patients with with null LDLR mutations seem to benefit from ANGPTL3 inhibitors, i.e. evinacumab. (*Pirillo A., Catapano A.L., Norata G.D. (2021). Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors. Current atherosclerosis* *reports, 23(12), 79.* [*[https://doi.org/10.1007/s11883-021-00972-x.)]*](https://doi.org/10.1007/s11883-021-00972-x.)) Evinacumab, a monoclonal antibody that inhibits ANGPTL3, is approved to treat homozygous familial hypercholesterolemia (HoFH). It targets angiopoietin-like 3 (ANGPTL3), and reduces LDL cholesterol by 49%.(Evinacumab---a therapy for homozygous familial hypercholesterolemia). Patients with refractory hypercholesterolemia, which is also a rare disorder in which a patient with FH (or occasionally other causes of high cholesterol) is unable to reach target cholesterol levels even after taking the highest tolerated doses of conventional cholesterol-lowering medications, have also shown promise with evinacumab(Evinacumab in Patients with Refractory Hypercholesterolemia). It achieves LDL-C reductions of up to 70% in cases where traditional therapies failed(Refractory Hypercholesterolemia in Heterozygous Familial Hypercholesterolemia Treated with Evinacumab). Although evinacumab provides a novel receptor-independent mechanism, it is advised that patients aged 5 and older with HoFH have it as an adjuvant therapy alonside existing lipid-lowering medications to improve overall lipid management. (*Complementary role of evinacumab in combination with lipoprotein apheresis in patients with homozygous familial hypercholesterolemia)(Treatment of Homozygous Familial Hypercholesterolemia With Evinacumab*) mAb like Ongericimab was also found out to reduce LDL-C levels in Chinese HoFH patients. (Abstract 10921: Efficacy and Safety of Ongericimab in Chinese Patients With Homozygous Familial Hypercholesterolemia). For high-risk patients, ANGPTL3 inhibitors are more cost-effective and effective, although they are not commonly accessible, and only a few European nations reimburse them for FH. Particularly in cases where HoFH treatment is not covered by insurance, more access is required. Yellow fever: ------------- Yellow fever (YF) is a life-threatening mosquito-borne flavivirus hemorrhagic fever (VHF) characterized by severe hepatitis, renal failure, hemorrhage, and rapid terminal events with shock and multi-organ failure.( https://doi.org/10.1016/j.antiviral.2007.10.009) Yellow fever virus is a neglected tropical disease and may be a potential future threat. (www.elsevier.com/locate/ijsu)Because of this sylvatic cycle, yellow fever cannot be eradicated except by completely eradicating the mosquitoes that serve as vectors. Yellow fever is a very rare cause of illness in U.S. travelers. ( https://www.cdc.gov/yellowfever/about/index.html.) Vaccination remains the cornerstone for preventing yellow fever, with the live attenuated 17D vaccine being widely used. mAbs were formed 17D using infected Vero cells. Antibodies identified antigenic domains in the YF virus envelope glycoprotein.mAbs were used in immunofluorescence tests to map antigenic domains and enhance diagnostic precision for YF and related flaviviruses. They demonstrated potential for identifying viral strains rapidly and for studying antigenic relationships and viral pathogenesis. (www.elsevier.com/locate/jcv) YFV-136 and YFV-121. Human mAbs were isolated from memory B cells of vaccinated person. YFV-136 targets the domain II (DII) of the YFV envelope protein, It neutralizes the virus at a post-attachment step, after the virus binds to host cells.Hamster models (against liver damage and viremia). And Immunocompromised mice engrafted with human hepatocytes mAbs demonstrated therapeutic protection YFV-136's neutralizing activity is consistent with antibodies elicited by the live-attenuated YFV vaccine, suggesting its role as a protective immune response in vaccinated individuals. (by Isolation of a Potently Neutralizing and Protective Human Monoclonal Antibody Targeting Yellow Fever Virus) Fibrodysplasia Ossificans Progressiva (FOP): -------------------------------------------- Fibrodysplasia ossificans progressive (FOP) is an extremely rare genetic connective tissue disorder characterized by the abnormal development of bone.(https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/) High-dose corticosteroids and anti-inflammatory drugs to manage inflammation in FOP. MAbs Garetosmab (GAR) neutralizes Activin A, a molecule that activates ACVR1, eƯectively preventing new bone formation.BLU-782 and DS-6016a antibodies that are experimently designed to inhibit ACVR1 gene. Anti-inflammatory Drugs Used to manage flare-ups and minimize inflammation-induced heterotopic ossification (HO).Small inhibitor molecule Target kinase activity of the mutant ACVR1/ALK2 receptor to prevent overactive BMP signaling.Examples: DMH1, which targets ALK1/2/3/6 kinase activity. (By Advances in biomedical research) The R206H mutation in the ACVR1/ALK2 gene alters the receptor's behavior, making it abnormally responsive to activin A, a ligand that does not typically activate the BMP pathway. This results in the phosphorylation of Smad 1/5/8 proteins and the transcription of osteogenic genes, driving heterotopic ossification (HO). Inflammatory processes further exacerbate this condition by activating activin A, amplifying HO via the mutant receptor. Therapeutic strategies focus on blocking ligand-receptor interactions with antibodies or ligand traps, inhibiting downstream Smad signaling, and modulating the immune response to reduce inflammation-driven HO. (http://dx.doi.org/10.21037/atm.2016.10.62) Giant cell tumor of bone: ------------------------- Giant cell tumor of bone is a rare, fast-growing non cancerous tumor. It most often grows in adults between ages 20 and 40 when skeletal bone growth is done. It is slightly more common in women.Giant Cell Tumor \| Johns Hopkins Medicine Giant cell tumour of bone (GCTB) is a benign osteolytic tumour with three main cellular components: multinucleated osteoclast-like giant cells, mononuclear spindle-like stromal cells (the main neoplastic components) and mononuclear cells of the monocyte/macrophage lineage. The giant cells overexpress a key mediator in osteoclastogenesis: the RANK receptor, which is stimulated in turn by the cytokine RANKL, which is secreted by the stromal cells. The RANK/RANKL interaction is predominantly responsible for the extensive bone resorption by the tumour. Historically, standard treatment was substantial surgical resection, with or without adjuvant therapy, with recurrence rates of 20--56 %. However, we have previously provided evidence, from functional and phenotypic studies of rodent and human osteoclasts, that raises the possibility that osteoclasts form a separate cell lineage from conventional hemopoietic cells and macrophages in particular.In an attempt to elucidate this question, we have used monoclonal antibody techniques to examine the relationship between osteoclastsmarrow-derived cells. A López-Pousa, J Martín Broto, T Garrido, J Vázquez But medical therapy with Denosumab (monoclonal antibody), an inhibitor of receptor activator of nuclear factor-κβ ligand, has become a component of patient management in select cases. Denosumab-treated giant cell tumor of bone (DT-GCTB) shows drastic morphologic changes including the presence of abundant bone.Darcy A Kerr, Iva Brcic, Julio A Diaz-Perez, Angela Shih, Breelyn A Wilky, Juan Pretell-Mazzini, Ty K Subhawong, G Petur Nielsen, Andrew E Rosenberg. Denosumab is an anti-RANKL monoclonal antibody approved for advanced or inoperable GCTB. It reduces tumor giant cells and induces histological changes but may complicate diagnosis due to stromal cell survival. Short-term denosumab administration achieves local control and functionality but prolonged use can lead to complications or local recurrence (LR). https://pmc.ncbi.nlm.nih.gov/articles/PMC9739142/ According to the 2020 World Health Organization classification, a giant cell tumor of bone is an intermediate malignant bone tumour. Nerve-sparing surgery after embolization is a possible treatment for giant cell tumors of the sacrum. Challenges associated with treatment of Monoclonal antibody: Denosumab reduces RANK-positive giant cells but not stromal cells, which may proliferate and cause bone destruction. Histological changes after denosumab treatment correlate with treatment duration. https://pmc.ncbi.nlm.nih.gov/articles/PMC9739142/ Clinical trials and case series have demonstrated that denosumab is relevant to beneficial tumor response and surgical down-staging in patients of GCTB. However, these trials or case series have limitations with a short follow-up. Recent increasing studies revealed that denosumab probably increased the local recurrence risk in patients treated with curettage. This may be caused by the thicken bone margin of tumor that trapped tumor cells from curettage. The direct bone formation by tumor cells in the margin after denosumab treatment also contributed to the local recurrence. More importantly, denosumab-treated GCTB exhibited morphologic overlap with malignancy, and a growing number of patients of malignant transformation of GCTB during denosumab treatment have been reported.Hengyuan Li, Junjie Gao, Youshui Gao, Nong Lin, Minghao Zheng, Zhaoming Ye A wait-and-see approach is recommended for lung metastases at first, then denosumab should be administered to the growing lesions. Shinji Tsukamoto, Andreas F Mavrogenis , Akira Kido, Costantino Errani. Myasthenia Gravis: Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder Renato Mantegazza, Francesco Saccà, Giovanni Antonini, Domenico Marco Bonifati, Amelia Evoli, Francesco Habetswallner, Rocco Liguori, Elena Pegoraro, Carmelo Rodolico, Angelo Schenone, Manlio Sgarzi, Giovanni Pappagallo Neurological Sciences, 1-13, 2024 Myasthenia Gravis (MG): ----------------------- Myasthenia Gravis (MG) is an autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ). These proteins include the nicotinic AChR or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering.Bianca M Conti-Fine, Monica Milani, Henry J Kaminski The Journal of clinical investigation 116 (11), 2843.. The spectrum of upcoming immunotherapies that more specifically address distinct targets of the main immunological players in MG pathogenesis includes T-cell directed monoclonal antibodies that block the intracellular cascade associated with T-cell activation, monoclonal antibodies directed against key B-cell molecules, as well as monoclonal antibodies against the fragment crystallizable neonatal receptor (FcRn), cytokines and transmigration molecules, and also drugs that inhibit distinct elements of the complement system activated by the pathogenic MG antibodies. Christiane Schneider-Gold, Nils Erik Gilhus Therapeutic advances in neurological disorders 14, 17562864211065406, Treatment includes anticholinesterase drugs, immunosuppression, immunomodulation, and thymectomy. The autoimmune response is maintained under control by corticosteroids frequently associated with immunosuppressive drugs, with improvement in the majority of patients. In case of acute exacerbations with bulbar symptoms or repeated relapses, modulation of autoantibody activity by plasmapheresis or intravenous immunoglobulins provides rapid improvement.The rationale for thymectomy relies on the central role of the thymus. Despite the lack of controlled studies, thymectomy is recommended as an option to improve the clinical outcome or promote complete remission. New videothoracoscopic techniques have been developed to offer the maximal surgical approach with the minimal invasiveness and hence patient tolerability. Renato Mantegazza, Silvia Bonanno, Giorgia Camera, Carlo Antozzi Neuropsychiatric disease and treatment, 151-160, 2011 Eculizumab and ravulizumab are monoclonal antibodies used to prevent complement‐mediated damage at the endplate of neuromuscular junction in MG with acetylcholine receptor (AChR) antibody. Neonatal Fc receptor (FcRn) antibodies including efgartigimod and rozanolixizumab are currently in different stages of clinical trial. The FcRn antibodies would be rational therapeutic agents for decreasing the levels of pathogenic autoantibodies with IgG isotypes, resulting in reduction in muscle‐specific kinase (MuSK) antibody as well as AChR antibody.But still it needs statistical data. Rituximab, a CD20+ B‐cell depleting monoclonal antibody, also results in a significant decrease in autoantibody titers in serum. Several studies indicate that rituximab may have the potential to treat MuSK‐MG. Monarsen, an antisense oligonucleotide, may reduce the production of acetylcholinesterase Tomihiro Imai Neurology and Clinical Neuroscience 7 (4), 161-165, 2019 Hemophilia: ----------- Hemophilia A is a hereditary condition that occurs in approximately 1 out of 5,000 male neonates. It is caused by deficiency of Factor VIII, a blood protein required for blood clotting because of a defect in the F8 gene located on the X chromosome. This condition is even more prevalent in male patients as opposed to female patients. It is a normal process that can prolong for years, including after surgeries or dental treatments. In severe cases, even minor cuts can cause prolonged bleeding, and there can be internal bleeding in vital organs, joints, and muscles (Franchini & Mannucci, 2012). The first monoclonal antibody (mAb) treatment for Hemophilia A, Emicizumab, was approved. This drug is bispecific, meaning it connects two clotting factors (FIX and FX) to mimic the function of Factor VIII and restore blood clotting. A Phase 3 clinical study showed that Emicizumab significantly reduced bleeding. The annual number of spontaneous bleeds dropped from 4.5 to 0.6, and target joint bleeds decreased from 1.7 to 1.0. The main side effect reported was a reaction at the injection site, seen in 22% of patients. The study concluded that Emicizumab effectively controls bleeding and is easy to tolerate, with a convenient dosing schedule once every four weeks. This lowers the burden of treatment (NCT03020160) (Mannucci, 2020). Humanized monoclonal anti-CD3 antibodies (α-CD3), such as teplizumab, otelixizumab, foralumab, and visilizumab, have effectively treated autoimmune diseases and prevented organ transplant rejection. These antibodies selectively bind to CD3ε and are less immunogenic than those employed in previous trials, which makes them less toxic and more palatable. Changes to the antibodies prevent overactivation of the immune system, like \"cytokine storms.\" Short-term intravenous α-CD3 treatment depletes T cells and increases Tregs, giving a temporary balanced state that helps in modulating immunopathology (Zimmerman & Valentino, 2013). Weiner and Herold suggested that since α-CD3 can be administered orally, it may not require specific antigens to activate the immune regulation process. Experiments on animal models of autoimmune diseases indicated that oral α-CD3 is effective in the gut and systematically to dampen immune reactions. This method does not involve the elimination of Tconv, but rather encourages the generation of Tregs with anti-inflammatory properties. Oral α-CD3 has also shown promise in treating conditions like atherosclerosis and non-alcoholic fatty liver disease (NASH) and preventing transplant rejection. The suppression mechanism involves regulatory T cells that release anti-inflammatory molecules like IL-10 and TGF-β (Konkle, 2017). However, the effect of oral α-CD3 on preventing the development of anti-drug antibodies (ADA) has not been studied much. Scientists hypothesized that oral α-CD3 could regulate specific helper T cells critical for producing high-affinity antibodies that neutralize therapies, such as factor VIII (FVIII) replacement therapy for hemophilia A. They tested this in mice with hemophilia A, comparing different doses and types of α-CD3 and exploring whether combining α-CD3 with an oral FVIII therapy (encapsulated in lettuce cells) would improve outcomes (Srivastava et al., 2020). The results showed that oral α-CD3 moderately reduced the formation of inhibitor antibodies during FVIII treatment. This suppression was linked to the early activation of regulatory T cells expressing specific markers (FoxP3, LAP, CD69, CTLA-4, and PD1). Combining α-CD3 with lettuce-encapsulated FVIII therapy did not show additional benefits, as both therapies appeared to work through separate mechanisms (Franchini & Mannucci, 2014). Rituximab, a chimeric monoclonal antibody targeting the CD20 protein on B cells, was first reported in 2001 as effective in treating inhibitors in acquired hemophilia A (AHA). So far, 160 patients with AHA treated with rituximab have been documented. Reviews by Franchini & Mannucci (2012) have summarized earlier studies, including cases mentioned only in abstracts, and this review provides updated information. Rituximab has been used either alone or with other immunosuppressive drugs, like steroids and cyclophosphamide, as either first-line or backup therapy. Overall, it showed a high success rate, with 77% of patients (123 out of 160) achieving complete recovery. Complete recovery typically means normal FVIII levels, no detectable inhibitors, or levels below 1 BU. In contrast, partial recovery involves a significant drop in inhibitor levels, FVIII levels above 25%, and no further bleeding. However, the criteria for defining complete or partial recovery vary between studies. This difference may explain the higher success rate in this review compared to others with stricter criteria. Many cases reported only positive outcomes, which may lead to overestimating success rates. These results should be interpreted carefully (Zimmerman & Valentino, 2013). Acquired  thrombotic thrombocytopenic purpura (aTTP): ----------------------------------------------------- Acquired Thrombotic Thrombocytopenic Purpura (aTTP) is a rare blood disorder affecting about 3.7 people per million each year. It causes small blood clots (thrombi) to form in tiny blood vessels throughout the body, reducing blood flow to important organs. This happens because the immune system reduces the activity of an enzyme called ADAMTS13, which breaks down von Willebrand factor (vWF). Without this enzyme, vWF sticks to platelets, forming clots that lead to low platelet levels (thrombocytopenia), anemia, and reduced blood supply to tissues (ischemia) (Peyvandi et al., 2016). Caplacizumab is a drug that blocks the interaction between vWF and platelets, helping to prevent clot formation. In a clinical trial (NCT02553317), Caplacizumab was found to normalize platelet counts faster than a placebo---taking 2.69 days on average compared to 2.88 days. The results of the trial showed that patients who received Caplacizumab had having normal platelet count than the placebo group with an odds ratio of 1.55. However the most frequently observed adverse effect associated with the drug was cutaneous/mucosal bleeding which affected 65% of the patients. In summary, the research noted that Caplacizumab is more effective in terms of speed, prevents aTTP relapse, and decreases mortality rates (Schaller et al., 2013). Neglected Tropical Diseases and Rare diseases: ============================================== Ebola Virus Disease: -------------------- Ebola virus causes a fatal Ebola Virus disease. It is NTD and a rare disease because of low incidence and high mortality rate, it has restricted geographical range of occurrence combined with lack of knowledge and investment. It can spread through direct human contact, throught cuts, abbrasions, contact with infected animals and infected blood and body fluids. It effects different immune cells like macrophages, antigen presenting cells (APCs) etc. It is characterized by fever, muscle pain, weight gain, hair loss, memory loss, multiple organ dysfunction syndrome etc. EBOV targets both innate and adaptive immunity and impairs the immune response and triggers inflammatory responses that causes load on immune system causing death beacaue of septic shock (TReatment of ebola virus disease). EBOV supresses immune system throught 8 viral proteins amoung them VP35, 24, 38, 39 are important. VP35 binds to double stranded RNA and triggers signaling pathways. It also attaches to STAT1 that is Signal Transducer and Activator of Interferons and mediates immune response.( good and bad faces of STAT1 in solid tumors). Reverse genetics has been used to identify targets that are important to cure and prevent the infection with EBAV. Non pathogenic but similar virus particles have been designrd through reverse genetics that has helped in studying the structure and mechanism of Ebola virus considering that Ebola is highly infectious and is dealt in BSL3.(Production of Novel Ebola Virus-Like Particles from cDNAs: an Alternative to Ebola Virus Generation by Reverse Genetics). Conventional Treatments include targeted antiviral compounds, small interfering RNA agents, favipiravir, immunotherapy, and other small molecules.(ebola virus infection a overview and update,treatment of Ebola Virus Disease) Ebola Zaire vaccine is an approved vaccine for preventing EBOV. Several Monoclonal Antibodies are used to treat the ebola virus disease. These include Atoltivimab, Porgaviximab, Ansuvimab (mAbs application in treatment 4097 download). 20 mAbs have been characterized. mAb114 is a single monoclonal antibody. Cocktails of mAbs are also utilized like MIL77E that has 2 antibodies combined, MB-003, 2Mab, ZMapp are cocktails of 3 mbAs.(Monoclonal antibodies for treatment of ebola pic). mAb114 was isolated from survivor of ebola (protective monotherapy against ebola pic), MIL77E is chimeric mbA from hamster and has 13C6 AND 2G4 mbAs in cocktail (two mAbs cocktail protects pic), MB-OO3 is human mouse chimeric antibody having 13C6, 6D8, 13F6 antibodies in cocktail that are immunoglobin(Ig) antibodies (epitopes involved in\-\-\-\--virun pic), 2Mab has 2G4,4G7,1H3 murine immunoglobin G(IgG) antibodies and ZMapp has 13C6, 2G4, 4G7 antibodies in cocktail, it is chimeric mouse-human antibody (mechanism of binding pic). mAbs bind to glycoprotein receptors on the surface of virus that is involved in attachment and fusion with host cells and prevents it from causing the infection. GP has 3 regions that are involved in mechanism of attachment and function of mbAs; GP base, a glycan cap or mucin like domain. REGN-EB3 and MAb114 has been proved to be effective mAbs during the Pamoja Tulinde Maisha (PALM) trial as these agents reduced the fatality rate among patients who got treatment immediately after appearance of symptoms.( monoclonal antibody therapy for ebola disease pic). Western Equine Encephalitis and Venezuelan Equine Encephalitis: --------------------------------------------------------------- Western Equine Encephalitis and Venezuelan Equine Encephalitis is caused by Western Equine Encephalitis Virus (WEEV) and Venezuelan Equine Virus (VEEV) respectively. WEEV is a rare disease because it is restricted to a specific geographical location, and because of lack of knowledge and understanding, lack of measures to control the mosquitos that act as vectors. VEEV is considered a neglected disease because of lack of knowledge and healthcare facilities. In the areas where is it prevalent the focus is on other diseases like TB leading to VEEV being neglected in these areas and also due to lack of measures to control mosquitos. Both are alpha viruses and are mosquito bourne, causing encephalitis i.e, inflammation of brain, in humans. They infect horses but horses are dead end host and the virus doesn't enter back into mosquitoes but can be transmitted through birds ( primary host). The mosquito when bites the infected primary hosts they become vector and carry the virus and infects humans upon biting. WEEV is found in north and south america (Western Equine Encephalitis submergence: Lack of evidence for a decline in virus virulence). Symptoms can range from illness to death. VEEV is epedemic in South America and is single stranted RNA and WEEV is chimeric formed by recombination of Eastern Equine Encephalitis Virus (EEEV) and sindbis virus (SINV) (venezuelan equine encephalitis virus a problem os not over, western equine encephalitis is a recombinant virus) There is no approved vaccine or drug for the treatment of WEEV and VEEV mostly supportive care like pain medications are provided and prevention is imposed. (Centre for disease control and prevention,2024, june 6, [[https://www.cdc.gov/wee/hcp/clinical-diagnosis-treatment/index.html)]](https://www.cdc.gov/wee/hcp/clinical-diagnosis-treatment/index.html)) A pyrazinecarboxamide derivative, T-705 commonly used against adenovirus is used for treatment of WEEV and targets Rna polymerase enzyme and causes its inhibition because of its similarity with adenivirus and its ability to increase the survival rate in mice although the treatment is not well established in humans. (Effect of T-705 treatment on western equine encephalitis in a mouse model). Against TC-83 an enantiomer of carbodine known as d-(-)- carbodine has shown to improve survival rate in mice but is yet to be well established for human use. (Treatment of Venezuelan equine encephalitis virus infection with (−)-carbodine). Monoclonal Antibodies offer a great opportunity in treatment of these diseases. The monoclonal antibodies tested against WEEV includes: ToR-3A2 that inhibits entry of virus in host, ToR-2C3 that is not a neutralizing antibody but is rather used for diagnostic purposes, ToR68-3G2 blocks the interaction of host and WEEV virus and prevents infection, ToR68-2E9 inhibits the onset of infection (human like antibodies neutralizing.....virus). Single domain antibodies like WC10,WC11f, WE10, WH11f, WH11, WB9,WF4 are used to neutralize the virus and also helps in diagnosis and detection. Recombinant antibodies scFr-Fc extracted from macaque bind to epitopes on envelope of virus. ScFv fragments from murine IgGs are used for diagnosis rather than neutralizing virus (selection of sdAbs towards weev). Monoclonal Antibodies against VEEV include ScFv fragments from human and murine sources (Human like antibodies neutralizing....virus), C1A3B-7 prevent the onset of disease in primates (therapeutic mAbs....aerosol exposure), Hu1A3B is a humanized antibody of murine 1A3B-7 antibody that bind to epitopes on the surface of virus and helps in neutralizing the virus. These monoclonal antibodies have shown to be effective in mice and need to be evaluated for effectiveness in humans to combat the disease outbreaks ( a humanized murine mAbs...against VEEV). Neglected Tropical Diseases (NTDs): =================================== Schistosomiasis( bilharzia): ---------------------------- It is a human parasitic disease caused by blood flukes( Schistoma) and is considered a neglected tropical disease because of lack of awareness, lack of ability to be diagnosed and in most cases especially in females it is often unreported. Its complexicity is because of the relation between human host and freshwater snail. The larva form of parasite called cercariae forms schistosomula in the body, and enters the lungs where they mature followed by entry into heart and intestines. The eggs are secreted in feaces and urine(recess). Prevalence of this disease is more common in Africa and Southeast Asia. It is included in neglected tropical diseases (NTD), is common in poor countries and children are most at risk. There are three strains; Schistosoma haematobium that is associated with urinary tract fibrosis common in Middle East and Africa and, S. mansoni common in central and South America and S. japonicum common in Eastern Asia, latter two causing chronic hepatic intestinal fibrosis.(Di Bella). Initial infection is associated with co-morbid infections like anemia and female genital schistosomiasis that also increases the risk of HIV (reasses). Conventional treatment of schistosomiasis includes Praziquantel (PZQ, pyrazino isoquinolone), effective treatment including single oral dose that is well tolerated and cost effective (CCO cite), chemotherapy (Persistent hotspot cite), mass drug administration that includes several administrations. Disappointingly there is no vaccine is available against schistosomiasis. (vaccine against helminths) Praziquantel, the ideal treatment kills 70-80% of the worms in humans after consuming regular dosage of 40-60mg and in mice 400mg kills 96% of the worms but the drug present in mice after administration of heavy dose was 6ng/ml which is 10 times higher that what was found in humans after regular dose administration because the increased dosage that recommended may increase toxicity and affects bioavailabilty in mice as humans absorb drugs differently meaning that the drug is less effective in humans as compared to mice as its not retained by the human body.(Harness) The novel treatment includes vaccination using monoclonal antobodies (mAbs) although further research is needed as there is no available mbAs for schistosomiasis. Only vaccines that have shown some effectiveness are still in clinical trials phases. A few of them include 1. 14kDa Fatty Acid Binding Proteins to target the pathway through which worm is dependent on host for faty acid as they last oxygen dependent process to synthesize them(cco). 2. Another one includes SJ18E which targets on glycoproteins receptors on the surface of worms( recess). 3. 28kDa glutathione S-transferase (sh28GST) that is important for parasites survival and is released to disrupt immune system. Vaccination involves forming recombinant sh28GST that activates immune system for better response and prevention ,(CCO) 4. Tetraspanins that targets teguments on the surface of parasites(CCO). Human African Trypanosomiasis (HAT): ------------------------------------ It is a parasitic disease caused by trypanosoma, endemic in Africa that spreads through vector called tsetse flies (blood sucking flies) and is called "Sleeping Sickness". It is considered an NTD because it is founded in areas where there is poverty and lack of knowledge, these areas are often disturbed by conflict causing lack of attention on the diseases, and teste flies that cause spread are difficult to control.HAT has two supspecies. Among the two subspecies Trypanosoma brucei gambiense is common in western and central africa's 24 countries and Trypanosoma brucei rhodesiense is common in eastern and western Africa's 13 countries. American trypanosomiasis, or [Chagas disease](https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)), is common in latin america and has different vector and characteristics. Nagana or animal trypanosomiasis is a disease in african cattle (WHO,2023). Trypanosoma brucei that is most common strain causing disease in humans has viral surface glycoprotein molecules (VSG) that are coded by different VSG genes therefore having variations and avoiding human immune response.(Degradation, Recycling, and Shedding of Trypanosoma brucei Variant Surface Glycoprotein pic). The conventional treatment includes a drug melersoprol that is a toxic drug. Another drug includes eflornithine but it is difficult to administer, nifurtimox is another oral and cheap drug but its effectiveness in HAT is not proven. Because of the prevalence of disease as endemic in Africa affecting central nervous system and resistance to available drugs there is need to develop new methods to combat the parasite causing the disease.( Treatment of human african disease present... pic) Novel approach to treat HAT is using monoclonal antibodies. Single dose of Antibody Conjugated Drugs (ACD) are used to treat Trypanosoma brucei by targeting haptoglobin-haemoglobin receptor (HpHbR) (hOW can mAbs harnessed). These receptors are not altered so is an effective method to counter the disease. Parasite obtains nutrients through these receptors. The idea is to deliver the drug attached with antibody that targets HpHbR similar to ACD drugs used in chemotherapy to treat cancers. One early attempt was to conjugate chrombucil to antibody derived from rabbit which was unsuccesful and another attempt is to attach apoL-1 toxic to nanobodies to target HpHbR. Recombinant human antibody conjugated with toxin PBD is also used to target HpHbR.(A single dose of antibody conjugate drug pic). Malaria: -------- *Plasmodium* protozoan that causes malaria is a serious public health concern that is mostly spread by female Anopheles mosquitoes carrying the infection. Malaria, which was once widespread in many places, including Poland, has become a sporadic problem in some places as a result of efficient management methods. Tropical and subtropical areas are primarily affected by the disease, which has serious consequences for vulnerable populations like children and expectant mothers.\ Because of its substantial impact on underprivileged communities---more than 241 million cases were reported in 2020---malaria is categorized as a neglected tropical disease (NTD). To fight malaria and other NTDs, big drug companies are investing more. (Drug firms invest in malaria and neglected tropical diseases) RTS,S, RTS,S/AS01 and R21vaccine, targets the fragment of circumsporozoite protein (CSP), a key parasite surface protein,( The RTS,S malaria vaccine). Despite the development of these vaccines, their limited effectiveness calls for supplementary approaches, such as high mAb titers. (https://doi.org/10.1016/S0140-6736(21)00943-0. and \ However, increasing research suggests that integrating other antigens in vaccination, such as i.e. thrombospondin-related anonymous protein (TRAP) or sporozoite surface protein 2 (SSP2), antigen from the pre-erythrocyte stage of the malaria parasite, could improve outcomes. Fusion proteins that combine TRAP and CSP, for example, have shown enhanced antigen synthesis and promise for successful vaccine development, even though they don\'t provide sterile protection by themselves.(Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines). There exists three types of mAbs that treat malaria based on the stage at which they atct upon, i.e., pre-erythrocytic stage, blood-stage and mosquito stage protein mAbs. Their mechanism of action includes direct inhibition, synergetic affects and sterile protection. ### Pre-Erythrocytic Stage (PE): ### Direct Inhibition: The pre-erythrocytic stage (PE) of malaria, involving the transition from sporozoites injected by the mosquito to their migration to the liver, presents a crucial opportunity for intervention mAbs. (Monoclonal antibodies for malaria prevention). These mAbs target various targets, e.g. CSP, CIS43, L9 and CelTOS, etc. ### CSP mAb: CSP is the primary target of malarial monoclonal antibodies. In animal models, mAbs against CSP have demonstrated the capacity to prevent hepatocyte invasion and lower liver burden, particularly for *Plasmodium falciparum* (Pf) and *Plasmodium yoelii.* (https://doi.org/10.1038/ S41598-021-84622-X. and [[https://journals.asm.org/doi/10.1128/iai.01249-13)).]](https://journals.asm.org/doi/10.1128/iai.01249-13)).) **CIS43 mAb**: A dual-binding antibody that targets the junctional and central repeat sequences of CSP, it exhibits encouraging protection in animal models. (Source: nm.4513, https://doi.org/10.1038.) Although modified CIS43LS has a longer half-life in serum and was safe in Phase I trials, the expense of high serum concentrations may restrict its long-term viability. (https://doi.org/10.1056/NEJMOA2034031.) **L9 mAb:** In clinical trials, the mAb L9LS demonstrated a 66% to 70% efficacy rate when compared to a placebo in preventing P. falciparum infections in children. This demonstrates how mAbs may be used as successful prophylactics in endemic areas. (Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.) (https://doi.org/10.1016/J.IMMUNI.2020.08.014.) **CelTOS**: Monoclonal antibodies like 7g7 and 4h12 target the cell traversal protein for ookinetes and sporozoites (CelTOS), a protein involved in Plasmodium movement. This provides multistage protection by limiting transmission to mosquitoes and preventing liver infections. Since sterile protection against P. falciparum and P. vivax is essential for thorough malaria control, these antibodies showed cross-species action. (Multistage protective anti-CelTOS monoclonal antibodies with cross-species sterile protection against malaria) **Synergistic Effect:** Since research shows that higher titers of anti-CSP antibodies correspond with a lower load of liver parasites, indicating a dose-dependent protective effect, RTS,S-induced antibodies may function in concert with mAbs. Malaria vaccines with very high antibody titers are promising, but depending only on them might not provide the high levels of sterile protection required to eradicate malaria. (https://doi.org/10.1016/S0140-6736(21)00943-0. and **Sterile Protection:** Additionally, research shows that when used in conjunction with anti-CSP antibodies, passive transfer of anti-TRAP mAbs may help maintain sterility, with protection exceeding 80% at low dosages in models of rodents and humanized liver mice.This lends credence to the multivalent vaccination approach, which seeks to increase protection by eliciting immune responses against several pre-erythrocytic antigens. Anti-TRAP/SSP2 monoclonal antibodies may improve protection by preventing sporozoite infection. (Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and may enhance protection of anti-CSP monoclonal antibodies) **Blood-Stage mAbs:** mAbs Monoclonal antibodies that target blood-stage antigens, such as MSP1, PfRH5, VAR2CSA, and PvDBP, have the potential to treat malaria, but they face obstacles such as antigen variation and high dose requirements. In order to improve efficacy and overcome these challenges, more research is required. **Blood-Stage mAbs:** mAbs that target mosquito-stage proteins, such as Pfs48/45, Pfs230, and TRIO, can stop the spread of malaria. Clinical trials are examining the effectiveness of these antibodies, and combining mAbs that target both parasites and mosquitoes may improve protection and aid in the eradication of malaria. Systemic Fungal Infections: --------------------------- Systemic fungal infections or Invasive Fungal Infections (IFI) are challenging to treat, especially in immunocompromised individuals, with high mortality of about 40% despite the availability of effective antifungal drugs. The reason for that is antifungal drug resistance upon prophylactic consumption and significant drug side effects. Monoclonal antibodies, alone (direct inhibition) or with antifungal drugs (synergetic effect), offer a promising solution to improve efficacy, overcome drug resistance and reduce toxicity. mAbs target fungal epitopes, mitigating host damage by inflammatory responses and enhancing immune defense mechanisms like cytokine release and phagocytosis.(Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies + reassess). Fungal infections are often neglected tropical diseases despite their significant impact on human health as they primarily affect poor populations with limited access to clean water, sanitation, and healthcare services. (Fungal diseases as neglected pathogens: A wake-up call to public health officials) ### Fungal Species and Their Effects: ***Cryptococcus spp.* (encapsulated yeasts)** Opportunistic infections, e.g. severe pulmonary and central nervous system (PNS and CNS) infections are caused by *Cryptococcus neoformans* and *Cryptococcus gattii*, especially in immunocompromised individuals (e.g. HIV/AIDS) especially in Sub-Saharan Africa( https://doi.org/10.1016/S1473-3099(17)30243-8). Traditional treatments include antifungal medications like fluconazole, amphotericin B, and 5-flucytosine. ***Paracoccidioides spp.*** Paracoccidioidomycosis is a systemic mycosis that is endemic in Latin America and is caused by *Paracoccidioides brasiliensis*. It majorly affects the lungs and has th epotential to spread resultimg in chronic disease. Antifungal therapy includes amphotericin B and itraconazole. ***Histoplasma spp.*** Histoplasmosis, a systemic mycosis contracted by spore inhalation, is caused by *Histoplasma capsulatum.* Although it mainly affects the lungs, immunocompromised people may spread it. Amphotericin B and itraconazole are examples of antifungal treatments. ***Sporothrix spp.*** *Sporothrix schenckii* causes sporotrichosis, that affects the skin and subcutaneous tissues. It is acquired through traumatic inoculation of fungal spores. It is obtained by traumatic fungal spore inoculation. The conventional treatment is itraconazole. ***Candida spp.*(major opportunistic fungal pathogen)** *Candida albicans* is capable of biofilm formation, resistance to antifungal medications, and adaptation to the in vivo environment. This makes it possible for its infections to vary from minor mucosal infections to potentially fatal systemic candidiasis. Amphotericin B, echinocandins, and fluconazole are examples of antifungal treatments. ***Aspergillus spp.*** The most frequent cause of invasive aspergillosis, especially in people with weakened immune systems, is Aspergillus fumigatus. This illness can spread to other organs and damages the lungs. Amphotericin B and voriconazole are common antifungal medications. ***Blastomyces spp.*** Blastomycosis is a systemic fungal infection that affects the lungs and can sometimes spread to other organs. It is caused by *Blastomyces dermatitidis*. Amphotericin B and itraconazole are examples of antifungal treatments. ----------------------------- ------------------------------- -------------------------------------------- -------------------------------------------------------------------------------------------------------- ------------------------------------- **Fungal Species** **Monoclonal Antibody (mAb)** **Target of mAb** **Mechanism of Action** **Approval Status** ***Cryptococcus spp.*** mAb 18B7 Capsular polysaccharide (GXM) Lowers serum GXM  levels and improves  fungal opsonization  and clearance. Discontinued after Phase I trials Mycograb® Heat shock protein 90 (HSP90) Improves fungus  clearance  synergetically with antifungal medications such as  fluconazole and mAB Development halted ***Paracoccidioides spp.*** mAb 3E gp43 glycoprotein Increases macrophage phagocytic activity, decreases fungal burden, and triggers Th1 cytokine response. Preclinical trail mAb B7D6 and C5F11 gp70 glycoprotein Improves macrophage-mediated clearance and promotes fungal killing through opsonization and Preclinical trail mAb 1G6 and 5E7C 75-kDa phosphatase Lowers granuloma size and fungal burden; regulates immune response to reduce inflammation. Preclinical trail ***Histoplasma spp.*** mAb against HSP60 Heat shock protein 60 Enhances phagocytosis and induces a Th1 immune response. Preclinical trail mAb against M antigen M antigen (glycoprotein) Promote opsonization of fungal cells, promoting enhanced phagocytosis and fungicidal activity. Preclinical trail mAb to melanin Melanin Reduces fungal resistance to phagocytosis, improves immunological clearance. Preclinical trail ***Sporothrix spp.*** mAb P6E7 70-kDa glycoprotein Improves phagocytosis, reduces fungal burden in organs, increases IFN-γ levels. Preclinical trail IgG2a mAb (MEST-3) Glycosphingolipids Prevent colony formation and inhibits fungal differentiation. Preclinical trail ***Candida spp.*** mAb C7 Als3p adhesin Direct fungicidal activity, inhibits adhesion, germination, and filamentation. Preclinical trail Mycograb® Heat shock protein 90 (HSP90) Synergizes with antifungal drugs to increase therapeutic efficacy. Reformulated variant in preclinical mAb 5H5 β-(1→3)-d-glucan Increases phagocytosis, facilitates fungal clearance, and synergizes with fluconazole. Preclinical trail mAb B6.1 β-1,2-mannotriose Synergizes with AmB and fluconazole to decrease fungal burden. Preclinical trail ***Aspergillus spp.*** mAb A9 95-kDa glycoprotein Inhibits fungal development and conidial germination. Preclinical trail mAb AK-14 Carbohydrate motif on fungal proteins Dcecreases fungal adhesion to host extracellular matrix proteins. Preclinical trail mAb R-5 Enolase Reduces fungal burden in animal models, inhibits spore germination,. Preclinical trail ***Blastomyces spp.*** 111In-400-2 mAb β-(1→3)-d-glucan Reduces fungal burden and kills cells by delivering radiolabeled payload to fungal cells. Preclinical trail ***Pneumocystis spp.*** mAb pool (IgG and IgM) Surface epitopes of Pneumocystis jirovecii Improves macrophage phagocytosis and controls inflammatory response. Preclinical trail ***Coccidioides spp.*** No mAb identified in trials \- Evidence of humoral response is limited; potential focus on cellular immunity for vaccine development. Research phase ----------------------------- ------------------------------- -------------------------------------------- -------------------------------------------------------------------------------------------------------- ------------------------------------- With few developments into human clinical trials, the majority of mAbs discussed are still at the preclinical stage. High production costs, a lack of accurate diagnostics to detect fungal infections early, and logistical difficulties with mAb administration and storage are among of the challenges. The above tables give us the impression that, despite its complexity, fungal immunomodulation has a lot of promise, and that more study is unquestionably needed to treat these dangerous infections.(Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies) Leishmaniasis: -------------- The protozoan parasite Leishmania major causes cutaneous leishmaniasis, preferentially attacks mononuclear phagocytic cells in its vertebrate host. There are 3 main forms of leishmaniases: visceral (the most serious form because it is almost always fatal without treatment), cutaneous (the most common, usually causing skin ulcers), and mucocutaneous (affecting mouth, nose and throat). Leishmaniasis, a neglected tropical disease often overlooked, affects an estimated 700,000 to 1 million people annually worldwide. (Is leishmaniasis donovani elimination feasible in Bhutan? A review of current prevention and control mechanisms in Bhutan. ) The FDA-approved treatment for leishmaniasis includes  intravenous liposomal amphotericin B (L-AmB) for VL and oral miltefosine for CL, ML, and VL caused by particular species.( *intravenous liposomal amphotericin B (L-AmB) for VL and oral miltefosine for CL, ML, and VL caused by particular species.*) In urine-based ELISA for visceral leishmaniasis (VL), monoclonal antibodies (mAbs) have a sensitivity of ≥93%, indicating their effectiveness in detecting Leishmania antigens. *(Urine-based antigen detection assay for diagnosis of visceral leishmaniasis using monoclonal antibodies specific for six protein biomarkers of Leishmania infantum / Leishmania donovani)*. Additionally, they are employed in piezoelectric immunosensors for the quick detection of L. infantum antigens.*(Detection of parasite antigens in leishmania infantum-infected spleen tissue by monoclonal antibody-, piezoelectric-based immunosensors)*. Recombinant camelid VHHs provide a promising substitute, reducing background noise while preserving sensitivity.*(Use of VHH antibodies for the development of antigen detection test for visceral leishmaniasis.).* Research done in 2017 aimed to develop monoclonal antibodies against Leishmania infantum\'s axenic amastigotes in Iran. Among the four positive hybridomas, the best clones, 6G2FV2 and 8D2FVI6, produced IgG2b subclass antibodies. These monoclonal antibodies specifically recognized the Iranian strain of L. infantum, marking a significant step in developing diagnostic tools for Kala-azar *(Development of monoclonal antibodies against axenic amastigotes of Leishmania infantum strain in Iran: implication for diagnosis of Kala-azar)*. Anti-L3T4 monoclonal antibody (mAb) treatment resulted in a significant reduction in lesion resolution and parasite load in BALB/c mice with cutaneous leishmaniasis; this effect was specific to anti-L3T4 mAb and was associated with the depletion of L3T4+ T cells in lymphoid tissues.*(THERAPEUTIC EFFECT OF ANTI-L3T4 MONOCLONAL ANTIBODY GK1.5 ON CUTANEOUS LEISHMANIASIS IN GENETICALLY-SUSCEPTIBLE BALB/c MICE)*. Monoclonal antibodies (mAbs) targeting different species of Leishmania have also demonstrated potential in preventing the development of Leishmania major in Phlebotomus duboscqi sand flies; the most effective mAbs tested were those against L. donovani (Ld2cb and Ld3A3), which inhibited parasite development by up to 82% Other mAbs showed lower inhibition.The results suggest that humoral immunity, mediated by specific mAbs, can play a role in its reduction.*(EFFECTS OF ANTI-LEISHMANIA MONOCLONAL ANTIBODIES ON THE DEVELOPMENT OF LEIHMANIA MAJOR IN PHLEBOTOMUS DUBOSCQI (DIPTERA: PSYCHODIDAE)*. While mAbs hold promise for improving Leishmania diagnosis, challenges like scalability and continuous supply remain. Further research is needed to enhance their clinical utility in leishmaniasis management. Hapititis B: ------------ Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). For most people, hepatitis B is short term, also called acute. Acute hepatitis B lasts less than six months. But for others, the infection lasts more than six months and is called chronic. Chronic hepatitis B raises the risk of liver failure, liver cancer and serious scarring of the liver called cirrhosis. (https://www.mayoclinic.org2) Hepatitis B is neglected tropical disease. The major burden of morbidity and mortality from HBV is now borne by tropical and subtropical countries. (https://doi.org/10.1371/journal.pntd.0005842) Pegylated interferon alpha (peg-IFN alpha) works by boosting the immune system to fight HBV and can lead to remission in some cases. However, its use is restricted due to potential side eƯects and safety concerns for certain patients. (https://www.wjgnet.com/2220-3249/full/v13/i1/88487.htm) N6HB426-20antibody targets human NTCP, a receptor essential for HBV entry into hepatocytes. It is eƯective in preventing HBV infection in vitro and in vivo. N6HB426-20 binds to specific extracellular loops of NTCP.NTCP is critical for HBV entry into host cells by interacting with the preS1 domain of the viral large surface protein. The antibody physically blocks HBV from attaching to NTCP, thereby preventing the virus from entering liver cells (hepatocytes). It neutralizes infection. In human liver chimeric mice, N6HB426-20 eƯectively prevents viremia for weeks post-HBV inoculation. (By Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection) Anti-CD20 agents: These include rituximab, ofatumumab, obinutuzumab, and ibritumomab, which target B lymphocytes by binding to the CD20 receptor. These drugs are eƯective but carry a high risk of HBV reactivation due to the suppression of humoral antibodies. ( [[https://www.wjgnet.com/2220-3249/full/v13/i1/88487.htm)]](https://www.wjgnet.com/2220-3249/full/v13/i1/88487.htm)) Bacterial Infections: --------------------- Animal derived antisera constituting polyclonal antibodies was used to treat bacterial infections before advent of antibiotics in 1930s. (Hey) Due to immunogenic disposition of animal antibodies and other proteins in antisera having tendency to evoke adverse reactions along with manufacture and distribution standardization difficulty, early treatments showed limitations (Sparrow E, Friede M, Sheikh M, et al.). Treatment faced paradigm shift with antibiotics introduction such as penicillin saving millions of humans and livestock (Marshall and Levy). But currently Antibiotic resistance has appeared as a challenge to public health due to rise in usage of antibiotics in some last decades (Ventola) (Wagner and Maynard) and bacterial pathogens mostly thriving in tropics are not properly categorized in neglected tropical diseases against which antimicrobial resistance has been developed. According to mechanism of bacterial pathogenicity, it colonizes and disturbs homeostasis of its host by producing toxic compounds. (Laustsen) Monoclonal antibodies (mABs) are safe and effective proteins produced in the laboratory that may be used to target a single epitope of a highly conserved protein of a virus or a bacterial pathogen. Monoclonal ABs can inhibit bacterial infections by neutralizing bacterial toxins and killing pathogenic bacteria. To specifically target bacterial toxic compounds and virulence factors, antibody based therapy has been developed. For example, human monoclonal antibodies; Bezlotoxumab against Clostridium difficile toxin B (Navalkele BD and Chopra T), Raxibacumab (Singh et al.) and Obiltoxaximab against Bacillus anthracis protective antigen; both are co-administered with antibiotics (Yamamoto et al.), Atidortoxumab against Staphylococcus aureus alpha toxin (Pelletier and Mukhtar), Raxibacumab against anthrax toxin-mediated cell damage through the inactivation of a component of the anthrax toxin (Kummerfeldt) and Obiltoxaximab against same anthrax toxin component as raxibacumab (Hou and Morrill). In most patients with chronic lung disease the emergence of resistance to antibiotics is a major obstacle to effective control of Pseudomonas aeruginosa (Pa) infections, mABs with potential activity against this pathogen were developed (Antonelli et al.). These treatments also have some challenges such as in case of Staphylococcus aureus (Sa), several mABs targeting bacterial antigens have been developed in recent years although none of them has been licensed for human use. (Sause et al.) In the future, other antibody formats and other routes of administration, as well as the use of DNA vaccines, may find their way to the market, both for human and veterinary indications. (Laustsen) RSV: ---- RSV is a common respiratory virus that causes mild to moderate cold-like symptoms mostly during fall, winter, and spring and usually in children years 5, adolescents, and adults (Coultas et al.). On the other hand, in infants and older adults it may cause very severe bronchiolitis and pneumonia leading to dangerous (Pickles and DeVincenzo), immediate and long-term dramatic medical, social and economic consequences. Preterm infants having congenital heart or chronic lung disease neuromuscular disorders or Down's syndrome are those at the highest risk. Although long acknowledged as one of the most common causes of upper respiratory tract infections (URI) in children since its discovery in 1956, the true burden of disease in adults is likely significantly under-recognized. The emerging evidence of RSV as a driver of morbidity and mortality in elderly and immunocompromised patients has sparked advances in vaccine development and renewed interest in quantifying the true burden of disease. (Busack and Shorr) According to estimates in 2015, RSV as a global burden caused over 30 million lower respiratory tract infections, specifically targeting children 5 years and younger, resulted in approximately 48,000 to 74,500 deaths as estimated in 2015(Shi et al.). Before the COVID-19 pandemic, it was estimated in USA that RSV caused in children \