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Computational Nanobody Design for Amyloid-Beta 42 Octamer in Alzheimer’s Disease

Introduction: Alzheimer’s disease is the most common type of neurodegenerative disorder, and amyloid-β (Aβ) plaques are associated with this disorder. According to the amyloid cascade hypothesis, the accumulation of neurotoxic Aβ42 generally plays a crucial role in the disease's progression. Emerging evidence shows that soluble oligomeric forms, especially tetramers and larger assemblies, are more neurotoxic than mature fibrils. Although several anti-Aβ antibodies target different states of aggregation (from monomers to plaques), nanobody-based therapies do not exist yet. Here, we aim to identify nanobodies targeting the Aβ42 octamer computationally.

Materials and Methods: A total of 40 nanobodies were modeled based on three enzymes known to interact with Aβ42. Using three Aβ42-interacting enzymes as templates, we designed 40 nanobody sequences through Essential Site Scanning Analysis, Peptide Atlas, and AbNatiV, with structural modeling performed via SWISS-MODEL and AlphaFold3. Then, a site-specific docking approach using ClusPro was performed to evaluate nanobody–Aβ42 binding, producing 120 nanobody–Aβ42 octamer complexes. They were ranked based on docking scores, salt bridge formation, stable interface interactions, and solvent-accessible surface area, narrowing the candidates down to seven promising complexes. This pipeline prioritized seven high-affinity candidates, which were further evaluated by conventional molecular dynamics (MD) simulations to assess complex stability.

Results: Among all screened complexes, a single nanobody exhibited persistent binding to the Aβ42 octamer, marked by prolonged interfacial contacts and minimal structural deviation. This candidate emerges as a potential diagnostic or therapeutic lead.

Conclusion: This study establishes an integrative computational framework for the systematic identification and evaluation of nanobodies targeting pathogenic amyloid aggregates, additionally offering a scalable strategy to prioritize high-affinity binders against disease targets.

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Signatures in Conformational Landscapes of Wild-Type and Mutant Shark VNARs Unveiled by Machine Learning and Essential Site Scanning Analysis

Introduction: Shark-derived single-domain antibodies (VNARs) exhibit unique structural adaptability, but the dynamic consequences of mutations remain poorly characterized. This computational study investigates how targeted mutations alter the conformational landscape of a VNAR, focusing on hypervariable (HVs), complementary-determining regions (CDRs), and framework (FW) residues critical for stability and function.

Methods: Conformational ensembles for the wild-type and mutant VNARs (with 13 mutations) in apo and complex lysozymes were generated using the ClustENMD unbiased sampling method, which integrates elastic network modeling, clustering, and molecular dynamics simulation. The ensembles were analyzed using Principal Component Analysis (PCA) to identify dominant motions; Linear Discriminant Analysis (LDA) and Random Forest were used to classify state-specific conformations and pinpoint residue-level discriminators. Centrality analyses of residue interaction networks were also applied to quantify changes in the VNAR allosteric communication. Additionally, the Essential Site Scanning Analysis (ESSA) was employed to identify potential allosteric sites on VNARs.

Results: PCA revealed divergent global dynamics, with the mutant exhibiting decreased flexibility. LDA identified several critical residues in the HV2, HV4, CDR1, CDR3, and FW3 that differ between the wild-type and mutant forms of VNAR, suggesting long-range allosteric effects. Central residues unique to the wild-type and mutant were extracted separately as a result of the centrality analyses, highlighting several residues in the five regions mentioned earlier, some of which overlap with those identified in the LDA findings. The Random Forest results also highlight the importance of HV4, FW3, and CDR3, in line with our ESSA results.

Conclusion: The mutations perturb VNAR dynamics predominantly in HV4, FW3, and CDR3 regions essential for antigen binding and structural integrity. These computational analyses not only decipher mutation-induced dynamical shifts, but also provide a blueprint for the rational design of stabilized VNARs. Our findings underscore FW3 as a potential allosteric regulator, offering new targets for engineering shark antibodies with enhanced therapeutic properties.

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Cryo-EM Structures of HCV E2 Bound to Neutralizing and Non-Neutralizing Antibodies Using Engineered Domain-Swapped Bivalent Fabs as Fiducial Markers
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The high-resolution cryo-EM of small antigen–antibody complexes remains a major challenge due to low molecular weight, conformational flexibility, and particle heterogeneity. To address this, we engineered a bivalent Fab from the broadly neutralizing antibody HC84.26.5D, which targets the hepatitis C virus (HCV) E2 glycoprotein. By deleting a single residue (VHSer113) in the Fab elbow region, we induced stable dimerization (~80% in solution) and confirmed dimer formation by solving its crystal structure at 1.8 Å resolution. The resulting Fab dimer adopts a domain-swapped conformation with ~25 Å separation between the VL/VH domains, forming a doughnut-shaped molecule with a rectangular central hole. This architecture enables the simultaneous binding of two E2 molecules and improves symmetry, effective mass, and particle alignment—key parameters for high-resolution cryo-EM reconstruction. Using this fiducial marker approach, we solved cryo-EM structures of E2 bound to three monoclonal antibodies with distinct neutralization profiles, a broadly neutralizing, moderately neutralizing, and non-neutralizing antibody, at resolutions of 3.8 Å, 3.3 Å, and 3.7 Å, respectively. Epitope mapping revealed that the broadly neutralizing antibody targets the conserved front layer of E2, while the non-neutralizing antibody binds to the back layer. Notably, the moderately neutralizing antibody spans both regions, defining a previously unrecognized cross-layer epitope associated with partial neutralization. This work establishes a generalizable strategy for domain-swapped Fab design that preserves antigen-binding integrity while enabling the structural analysis of small or flexible antigen–antibody assemblies by cryo-EM. In addition, it provides mechanistic insights into how epitope location influences neutralization potency, offering a molecular blueprint for rational HCV vaccine design focused on conserved, functionally critical epitopes of E2.

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Monoclonal Antibodies in Cervical Cancer: Advancing Targeted Immunotherapy
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Cervical cancer remains one of the leading causes of cancer-related mortality among women worldwide, particularly in developing countries. While early screening and HPV vaccination have significantly reduced incidence rates, advanced and recurrent stages of cervical cancer still pose major treatment challenges. Conventional therapies such as chemotherapy and radiotherapy often result in systemic toxicity and limited efficacy. In this context, monoclonal antibodies (mAbs) have emerged as a powerful and targeted therapeutic option, capable of offering greater precision with fewer side effects.

Monoclonal antibodies are engineered proteins that bind specifically to antigens expressed on tumor cells or within the tumor microenvironment. In cervical cancer, several key targets have been identified, including vascular endothelial growth factor (VEGF) and programmed death-ligand 1 (PD-L1). The anti-VEGF mAb bevacizumab was the first to be approved for advanced cervical cancer and has shown to significantly improve progression-free and overall survival when combined with chemotherapy by inhibiting tumor angiogenesis.

Checkpoint inhibitors such as pembrolizumab and nivolumab, which target the PD-1/PD-L1 axis, have demonstrated promising results in restoring T-cell activity and enhancing immune-mediated tumor cell killing in patients with recurrent or metastatic disease. These immune-based therapies mark a paradigm shift toward precision oncology in cervical cancer treatment.

Furthermore, antibody–drug conjugates (ADCs) represent an evolving strategy, combining monoclonal antibodies with potent cytotoxic drugs to deliver targeted therapy directly to cancer cells. Emerging targets such as tissue factor (TF) and epidermal growth factor receptor (EGFR) are currently under clinical investigation to further expand the treatment arsenal.

This paper explores the structural and functional aspects of monoclonal antibodies in the context of cervical cancer, detailing their mechanisms, clinical relevance, and future prospects. With continued research and development, monoclonal antibodies are poised to redefine the therapeutic landscape of cervical cancer by offering safer, more effective, and personalized treatment options.

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The Art of Immune Suppression: An Antibody Perspective
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The immune system serves as the body’s defense mechanism against pathogens and abnormal cells. However, in autoimmune conditions or transplant scenarios, it becomes essential to suppress the immune response to prevent tissue damage or graft rejection. This delicate balance is achieved through targeted immunosuppressive therapies. Antibodies, particularly monoclonal and engineered types, have emerged as potent tools in this domain, offering precision in modulating immune activity while minimizing generalized immunosuppression.

In diseases such as Neuromyelitis Optica Spectrum Disorder (NMOSD), where the immune system mistakenly targets the aquaporin-4 water channels in the central nervous system, antibody-mediated immune suppression plays a pivotal role. Drugs like eculizumab, a complement inhibitor, and inebilizumab, an anti-CD19 monoclonal antibody, exemplify the effectiveness of tailored antibody therapies in mitigating disease progression while preserving general immune function.

The need for immune suppression arises not only in autoimmune conditions but also in organ transplantation, allergic reactions, and certain chronic inflammatory diseases. Traditional immunosuppressants affect multiple immune pathways, often leading to an increased risk of infections and malignancies. In contrast, antibody-based suppression provides a targeted approach—binding to specific immune cells, receptors, or cytokines to downregulate overactive responses.

However, concerns remain regarding long-term safety and immune compromise. The prolonged use of immune-suppressing antibodies can lead to opportunistic infections, diminished vaccine response, and the reactivation of latent diseases. Yet, with proper dosing, monitoring, and patient stratification, these risks can be significantly reduced. Clinical trials and post-marketing surveillance have shown that with correct protocols, antibody-based immune suppression does not inherently pose a major threat, especially when compared to conventional immunosuppressive regimens.

In conclusion, antibodies offer a sophisticated means to modulate the immune system, addressing critical medical needs with increasing safety and specificity. Their role in diseases like NMOSD showcases how targeted suppression can lead to improved outcomes without broadly compromising immune defense.

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Advancements in Antibody Technology: From Bispecifics to AI-Driven Therapeutics
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Antibody technology has rapidly evolved beyond conventional monoclonal antibodies, transforming the landscape of diagnostics, immunotherapy, and precision medicine. These advancements have led to the development of highly specialized antibody formats and engineering platforms that address complex diseases, including cancers, viral infections, and autoimmune conditions.

One of the most significant breakthroughs is the development of bispecific antibodies, which are designed to simultaneously bind to two different antigens or epitopes. This dual-targeting capability enhances therapeutic specificity, as seen in bispecific T-cell engagers (BiTEs), which redirect immune cells to tumor cells, offering greater efficacy in cancer immunotherapy.

Antibody-drug conjugates (ADCs) represent another innovation, combining the specificity of antibodies with the potency of cytotoxic agents. By selectively delivering chemotherapy drugs to tumor cells, ADCs such as trastuzumab deruxtecan have shown marked success in treating HER2-positive cancers, with reduced systemic toxicity.

During the COVID-19 pandemic, antibody technology played a pivotal role in the development of neutralizing antibodies against SARS-CoV-2. Monoclonal antibodies targeting the spike protein helped reduce viral load and disease severity in infected patients, demonstrating the rapid applicability of antibody platforms in pandemic response.

AI-driven antibody design is emerging as a revolutionary approach in drug development. Machine learning algorithms are being used to predict antibody–antigen interactions, optimize binding affinities, and design novel antibody sequences with high precision and speed, significantly reducing time and cost in therapeutic discovery.

Moreover, CAR T-cell therapy, a form of cellular immunotherapy based on engineered antibodies, has shown remarkable success in treating hematologic malignancies. By fusing an antibody-derived recognition domain with a T-cell signaling domain, CAR T-cells specifically target and kill cancer cells, offering durable responses in refractory cases.

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Smart Weapons Against Cancer: The Role of Monoclonal Antibodies in Targeted Therapy
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Monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy by offering highly specific, targeted treatment options that differ significantly from conventional chemotherapeutic approaches. These laboratory-engineered antibodies are designed to recognize and bind selectively to antigens expressed on the surface of cancer cells, leading to direct or immune-mediated tumor cell destruction.

The therapeutic mechanisms of mAbs include blocking growth factor receptors, inducing apoptosis, recruiting immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and delivering cytotoxic agents via antibody–drug conjugates (ADCs). Notable examples include trastuzumab, which targets the HER2 receptor in breast cancer, and rituximab, which binds to CD20 in non-Hodgkin’s lymphoma. These treatments have significantly improved clinical outcomes, including progression-free survival and overall response rates.

Monoclonal antibodies can be classified based on their function: naked antibodies that act without a drug payload; conjugated antibodies linked to toxins or radionuclides; and bispecific antibodies designed to bind to two different antigens simultaneously. Additionally, immune checkpoint inhibitors such as nivolumab and pembrolizumab block PD-1/PD-L1 pathways, restoring the immune system’s ability to recognize and attack cancer cells.

Ongoing research in molecular oncology and immunotherapy is paving the way for personalized cancer therapy, in which monoclonal antibodies are selected based on the genetic and molecular profile of the tumor. Despite their success, challenges remain, including tumor antigen heterogeneity, resistance development, and adverse immune reactions.

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Architects of Immunity: Structural Insights into Antibodies for Novel Biomedical Applications

Antibodies, or immunoglobulins, are Y-shaped glycoproteins produced by B cells, playing a central role in immune defense. Their unique structural characteristics, particularly the variable (V) and constant (C) regions, have made them indispensable not only in traditional immunology, but in a broad spectrum of modern biomedical applications. Advances in structural biology and protein engineering have enabled the rational design of antibody-based tools for diagnostics, therapeutics, and targeted drug delivery.

The antigen-binding fragment (Fab) of an antibody, comprising variable regions of the heavy and light chains (VH and VL), is responsible for high-affinity binding to specific epitopes. Meanwhile, the crystallizable fragment (Fc) mediates effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation. Modifications in these regions allow for tailoring antibodies to specific therapeutic needs, including half-life extension, reduced immunogenicity, or enhanced tissue penetration.

In novel applications, structural insights have facilitated the development of single-chain variable fragments (scFvs), nanobodies, and bispecific antibodies, offering reduced size, improved tissue access, and dual-targeting capabilities. These engineered formats are now being explored in targeted cancer therapies, neurodegenerative disease treatment, biosensor design, and infectious disease management. The understanding of hinge flexibility, epitope–paratope interactions, and glycosylation patterns has further enhanced the functional versatility of antibodies.

Monoclonal antibodies, owing to their specificity and modularity, are now employed in precision medicine, including checkpoint blockade therapy, antibody-drug conjugates (ADCs), and CAR-T cell engineering. Moreover, structural mapping using tools such as X-ray crystallography, cryo-electron microscopy, and molecular dynamics simulations is paving the way for the next generation of antibody-based modalities.

This work explores the structural foundations that empower antibodies to serve as precision instruments in diverse biomedical fields. By integrating structural design with innovative applications, antibodies are transitioning from natural immune defenders to engineered molecules with immense therapeutic and diagnostic potential.

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Antibodies in the War Against Cancer: Precision Weapons in Targeted Therapy
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Among the arsenal of therapeutic strategies, antibodies have emerged as potent tools in the war against cancer due to their exceptional specificity and adaptability. Antibodies are protective glycoproteins that are synthesized by the immune system in response to foreign substances known as antigens. Their unique ability to selectively recognize and bind to tumor-associated antigens has positioned them as a cornerstone in targeted cancer therapy.
The mechanism by which antibodies act against cancer cells can be either direct—by inducing apoptosis or inhibiting cellular proliferation—or indirect, by recruiting immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Monoclonal antibodies (mAbs), the most commonly used therapeutic format, have shown considerable success in treating cancers such as breast cancer (e.g., trastuzumab) and lymphomas (e.g., rituximab). Based on their structure and action, antibody therapies can be classified into naked antibodies, conjugated antibodies (linked to toxins or radionuclides), immune checkpoint inhibitors, and engineered formats such as bispecific and trispecific antibodies, which can bind to two or more targets simultaneously, thereby enhancing therapeutic outcomes.
Personalized antibody therapy has gained momentum, guided by tumor profiling and molecular diagnostics. This approach enables the selection of antibody treatments based on the unique genetic and proteomic signature of an individual’s tumor, ensuring improved efficacy and minimized toxicity. Moreover, combining antibodies with chemotherapy, radiotherapy, or other immunotherapies (like CAR-T cells or checkpoint inhibitors) offers synergistic effects and overcomes tumor resistance.

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Targeted Drug Delivery in Lung Cancer Using Antibodies: A Precision Approach to Therapy
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Lung cancer remains one of the most prevalent and lethal cancers worldwide, often diagnosed at advanced stages with limited therapeutic success. Conventional chemotherapies, though widely used, lack selectivity and are associated with systemic toxicity and multidrug resistance. In recent years, antibody-mediated targeted drug delivery systems have emerged as promising strategies to enhance treatment specificity and efficacy in lung cancer.

Monoclonal antibodies (mAbs) serve as precision tools for identifying and binding to specific antigens expressed on the surface of cancer cells, allowing for selective delivery of therapeutic agents while sparing healthy tissues. Antibodies directed against targets such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and PD-L1 are being extensively studied and applied in non-small cell lung cancer (NSCLC), the most common subtype of lung cancer.

Antibody-drug conjugates (ADCs) represent a breakthrough in targeted drug delivery by coupling potent cytotoxic drugs to tumor-specific antibodies. These conjugates ensure that the drug is internalized by cancer cells after antigen binding, releasing the payload intracellularly to induce apoptosis. Notable examples include trastuzumab deruxtecan and patritumab deruxtecan, which are under investigation for HER2-positive lung cancer.

In addition to ADCs, antibodies are also used to deliver nanoparticles, liposomes, or gene therapy vectors directly to tumor sites, enhancing the bioavailability and retention of drugs in the tumor microenvironment. These innovations not only increase therapeutic efficiency but also reduce off-target effects.

Furthermore, the integration of immune checkpoint inhibitors such as nivolumab and atezolizumab, which block PD-1/PD-L1 signaling, has transformed immunotherapy in lung cancer, restoring anti-tumor immune responses and improving overall survival in selected patients.

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