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Advancements in antibody-drug conjugates as cancer therapeutics.

Antibody-drug conjugates (ADCs) represent a promising approach in targeted cancer therapy, combining the targeted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst minimising off-target effects. This review provides a comprehensive analysis of ADCs, encompassing their structural components, mechanisms of action, and clinical applications. It also examines recent technological advancements, particularly in antibody engineering and linker design, aimed at enhancing therapeutic efficacy and safety. The current clinical landscape is outlined, h

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… Decreased penetration and abnormal endosomal transit have been suggested, as increased cellular barriers, and altered uptake pathways can impede ADCs from entering the cell. 136 , 137 A different mechanism of uptake from the common clathrin-mediated pathway was found, as they discovered that ADC was …

Antibody drug conjugates in the clinic.

Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer

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… resulting in only a small fraction (0.0003%–0.08% per gram of tumor 31 ) of the administered dose eventually accumulating at the target site, underscoring the need for a highly potent payload. 32 The binding of the antibody to its target triggers the internalization of the ADC, which can occur via clathrin‐mediated …

Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research.

Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles t

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… The liposomes were fully characterized, and in vitro studies showed that immunoliposomes entered the targeted cells via clathrin-dependent uptake, and a correlation between cellular GD2 levels and the ability to target cells using etoposide-containing immunoliposomes was observed [ 134 ]. …

Immunological Approaches Towards Cancer and Inflammation: A Cross Talk.

The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful. The acute inflammatory response tends to resolved once the offending agent is subside but this acute response becomes chronic in nature when the body is unable to successfully neutralized the noxious stimuli. This chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and oncogenic mediators such as nitric oxide (NO), cytokines [IL-1β, IL-2, interleukin-6 (IL-6), and tumor necrosis factor-α

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… This compound mediates it anticancer activity via uptake into (i) glycan binding on the cell surface; (ii) clathrin-dependent and -independent endocytosis; (iii) redirection of the protein from endocytic vesicles to Golgi network and presumably its subsequent retrograde transport to the ER ( 161 ). …

Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting.

Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanopar

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… In addition, caveolin-mediated and caveolin-/clathrin-independent endocytosis facilitated the intestinal absorption of DOX. …

Imiglucerase in the treatment of Gaucher disease: a history and perspective.

The scientific and therapeutic development of imiglucerase (Cerezyme(®)) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ul

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… These are highly conserved monomeric clathrin adaptor proteins that orchestrate the trafficking of the mannose 6-phosphate receptors and other cargo molecules from the trans-Golgi network to the endosome-lysosome system. …

The next frontier in antibody-drug conjugates: challenges and opportunities in cancer and autoimmune therapy.

Antibody-Drug Conjugates (ADCs) have achieved significant success in cancer therapy by combining the targeting specificity of monoclonal antibodies with cytotoxic payloads. However, the concomitant issue of drug resistance has become increasingly prominent, with primary mechanisms including alterations in target antigen expression, impaired drug transport, and inhibition of cell death pathways. ADCs have also shown emerging therapeutic potential in the treatment of autoimmune diseases; for instance, ABBV-3373 has achieved initial success in this area, yet it also faces unique challenges such a

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… Under normal conditions, most ADCs enter lysosomes via clathrin-mediated endocytosis. However, resistant cells can alter this pathway, leading to resistance [ 108 , 110 , 116 ] . …

Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance.

Chemotherapy is an effortless and frequently used approach in cancer therapy. However, in most cases, it can only prolong life expectancy and does not guarantee a complete cure. Furthermore, chemotherapy is associated with severe adverse effects, one of the major complications of effective cancer therapy. In addition, newly published research outputs show that cancer stem cells are involved in cancer disease progression, drug resistance, metastasis, and recurrence and that they are functional in the trans-differentiation capacity of cancer stem cells to cancer cells in response to treatments.

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… spike (S) protein cleavage at the angiotensin-converting enzyme 2 (ACE2) binding site, and prevention of cytokine storm 5 | Chlorpromazine 175 | Originally synthesized as an antimalarial | Used as sedative-anxiolytic in acute mania as an adjunct to barbiturates and later also for Covid-19 | Inhibit clathrin-mediated …

An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer.

Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With thi

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… These nanocarriers targets mitochondria by using different fate and mechanisms which includes macropinocytosis, caveolae-mediated endocytosis, phagocytosis, clathrin-mediated endocytosis, membrane fusion, receptor and protein-mediated, mitochondrial transmembrane-potential mediated accumulation, glutathione …

Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus.

Angiogenesis is the biological process by which new blood vessels are formed from pre-existing vessels. It is considered one of the classic hallmarks of cancer, as pathological angiogenesis provides oxygen and essential nutrients to growing tumors. Two of the seven known human oncoviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), belong to the Gammaherpesvirinae subfamily. Both viruses are associated with several malignancies including lymphomas, nasopharyngeal carcinomas, and Kaposi's sarcoma. The viral genomes code for a plethora of viral factors, includin

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… EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog. 9:e1003510. 10.1371/journal.ppat.1003510 Dwyer J., Le Guelte A., Galan Moya E. …

Pathogenesis and kidney prognosis of renal amyloidosis.

Light chain (AL), serum amyloid A (AA), transthyretin (ATTR), leukocyte cell derived chemotaxin 2 (ALECT2), and fibrinogen Aa (AFib) amyloidosis are some of the most common types of protein-deposition disorders involving the kidney. Each amyloidogenic protein differs in its origin and little is known about the exact mechanisms that govern renal tropism and tissue injury for each amyloid subtype. While amyloidogenic precursor protein is different in each subtype of amyloidosis, its aggregation into fibrils depositing in target organs and leading to disruption of tissue architecture and progress

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… Mesangial cells endocytose amyloidogenic light chain through clathrin mediated mechanisms which are then intracellularly trafficked through the endolysosomal system with the assistance of Rab family proteins [ 21 , 24 – 27 ]. …

Cancer immunotherapies: A hope for the uncurable?

The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are cruc

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… After initial binding, the pentons in the adenovirus interact with the host-cell integrins (α v β 3 or α v β 5 ), leading to activation of certain signaling proteins (GTPases, phosphoinositide-3-OH kinase and MAPK) which induce the uptake of the virus particles via clathrin-coated vesicles ( Wickham …

Resveratrol Nanoformulations for Cancer Management: A Comprehensive Review of Disease-Specific Strategies and Clinical Translational Barriers.

Cancer remains a leading cause of mortality worldwide, highlighting the need for therapeutic strategies that reduce systemic toxicity and drug resistance. Resveratrol (RES), a natural polyphenolic stilbenoid, possesses antioxidant, anti-inflammatory, pro-apoptotic, anti-metastatic, and chemosensitizing activities. However, its clinical translation is limited by poor aqueous solubility, chemical instability, rapid metabolic clearance, and consequently low systemic bioavailability. Nanotechnology-based drug delivery systems provide a promising strategy to address these limitations. This review s

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… stimuli-responsive carriers, while ultrasmall (<50 nm), near-neutral particles retain a penetration advantage. 73 Cellular Internalization and Intracellular Trafficking Even upon reaching the tumor cell surface, nanocarriers must overcome the plasma membrane barrier through endocytic uptake—most commonly via clathrin-mediated …

Nanoparticles Based Therapeutic Approaches in Oncogenic Viral Infections: A Review.

Nanotechnology has revolutionized biomedical research by providing novel strategies for the prevention, diagnosis, and treatment of oncogenic viral infections. Nanoparticles, possessing tunable physicochemical properties, enable targeted drug delivery, enhance vaccine efficacy, and facilitate advanced viral diagnostics, addressing key limitations of conventional therapies. Oncogenic viruses contribute substantially to the global burden of cancer through persistent infections and are influenced by environmental and lifestyle factors. The objective of this review is to synthesize and critically

A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy.

Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment of hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, that are mainly associated with modest specificity and therapeutic benefit, the three key components that form an ADC (a monoclonal antibody bound to a cytotoxic drug via a chemical linker moiety) achieve remarkable improvement in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tum

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… After interacting with its target, Adcetris enters the endosomal/lysosomal pathway via clathrin-dependent endocytosis, where its linker is cleaved by acid hydrolases to release MMAE in the cytoplasm. The drug interferes with microtubule polymerization and induces apoptosis and cell death. …

COVID-19 and Cancer Comorbidity: Therapeutic Opportunities and Challenges.

The coronavirus disease 2019 (COVID-19) is a viral disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the respiratory system of infected individuals. COVID-19 spreads between humans through respiratory droplets produced when an infected person coughs or sneezes. The COVID-19 outbreak originated in Wuhan, China at the end of 2019. As of 29 Sept 2020, over 235 countries, areas or territories across the globe reported a total of 33,441,919 confirmed cases, and 1,003,497 confirmed deaths due to COVID-19. Individuals of all ages are at risk for infec

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… For example, mouse hepatitis coronavirus (MHV) enters the cells through clathrin-mediated endocytosis and later moves to lysosomes due to the fusion of endosomes with lysosomes. …

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses.

The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term wi

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… Endosomal features that can be targeted are virus particle internalization (e.g., via clathrin or macropinocytosis) as well as endosome trafficking, maturation, and composition, including low pH, cathepsin proteases, Ca 2+ and other ions, and specific lipids ( 171 – 173 ). …

Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer.

Cancer represents a group of heterogeneous diseases characterized by uncontrolledgrowth and spread of abnormal cells, ultimately leading to death. Nanomedicine plays a significantrole in the development of nanodrugs, nanodevices, drug delivery systems and nanocarriers. Someof the major issues in the treatment of cancer are multidrug resistance (MDR), narrow therapeuticwindow and undesired side effects of available anticancer drugs and the limitations of anticancerdrugs. Several nanosystems being utilized for detection, diagnosis and treatment such as theranosticcarriers, liposomes, carbon nano

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… The complex internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis and was eventually delivered into the mitochondria. 2.6.3. Graphene Oxide GO was extensively used in a wide variety of applications including antibacterial and anticancer agents. …

Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities.

New-generation vaccines, formulated with subunits or nucleic acids, are less immunogenic than classical vaccines formulated with live-attenuated or inactivated pathogens. This difference has led to an intensified search for additional potent vaccine adjuvants that meet safety and efficacy criteria and confer long-term protection. This review provides an overview of protein-based adjuvants (PBAs) obtained from different organisms, including bacteria, mollusks, plants, and humans. Notably, despite structural differences, all PBAs show significant immunostimulatory properties, eliciting B-cell- a

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… Similarly, we have observed that hemocyanins directly bind to CRDs in the MR and DC-SIGN (a DC-specific ICAM-3–grabbing nonintegrin) with high affinity constants, colocalizing with these receptors after being internalized into human DCs through clathrin-mediated endocytosis [ 104 ]. …

COVID-19 Therapeutic Options Under Investigation.

Since its emergence in China in December 2019, COVID-19 has quickly spread around the globe causing a pandemic. Vaccination or the development of herd immunity seems the only way to slow down the spread of the virus; however, both are not achievable in the near future. Therefore, effective treatments to mitigate the burden of this pandemic and reduce mortality rates are urgently needed. Preclinical and clinical studies of potential antiviral and immunomodulatory compounds and molecules to identify safe and efficacious therapeutics for COVID-19 are ongoing. Two compounds, remdesivir, and dexame