A novel SLC3A2-targeting antibody-drug conjugate exerts potent antitumor efficacy in head and neck squamous cell cancer.

The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.

Improved antitumor effects elicited by an oncolytic HSV-1 expressing a novel B7H3nb/CD3 BsAb.

Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.

Development of therapeutic antibodies for the treatment of diseases.

Since the first monoclonal antibody drug, muromonab-CD3, was approved for marketing in 1986, 165 antibody drugs have been approved or are under regulatory review worldwide. With the approval of new drugs for treating a wide range of diseases, including cancer and autoimmune and metabolic disorders, the therapeutic antibody drug market has experienced explosive growth. Monoclonal antibodies have been sought after by many biopharmaceutical companies and scientific research institutes due to their high specificity, strong targeting abilities, low toxicity, side effects, and high development success rate. The related industries and markets are growing rapidly, and therapeutic antibodies are one of the most important research and development areas in the field of biology and medicine. In recent years, great progress has been made in the key technologies and theoretical innovations provided by therapeutic antibodies, including antibody-drug conjugates, antibody-conjugated nuclides, bispecific antibodies, nanobodies, and other antibody analogs. Additionally, therapeutic antibodies can be combined with technologies used in other fields to create new cross-fields, such as chimeric antigen receptor T cells (CAR-T), CAR-natural killer cells (CAR-NK), and other cell therapy. This review summarizes the latest approved or in regulatory review therapeutic antibodies that have been approved or that are under regulatory review worldwide, as well as clinical research on these approaches and their development, and outlines antibody discovery strategies that have emerged during the development of therapeutic antibodies, such as hybridoma technology, phage display, preparation of fully human antibody from transgenic mice, single B-cell antibody technology, and artificial intelligence-assisted antibody discovery.

Development of an autophagy activator from Class III PI3K complexes, Tat-BECN1 peptide: Mechanisms and applications.

Impairment or dysregulation of autophagy has been implicated in many human pathologies ranging from neurodegenerative diseases, infectious diseases, cardiovascular diseases, metabolic diseases, to malignancies. Efforts have been made to explore the therapeutic potential of pharmacological autophagy activators, as beneficial health effects from caloric restriction or physical exercise are linked to autophagy activation. However, the lack of specificity remains the major challenge to the development and clinical use of autophagy activators. One candidate of specific autophagy activators is Tat-BECN1 peptide, derived from Beclin 1 subunit of Class III PI3K complexes. Here, we summarize the molecular mechanisms by which Tat-BECN1 peptide activates autophagy, the strategies for optimization and development, and the applications of Tat-BECN1 peptide in cellular and organismal models of physiology and pathology.

Graphene oxide and sulfonated polyanion co-doped hydrogel films for dual-layered membranes with superior hemocompatibility and antibacterial activity.

In this study, a new kind of hemocompatible and antibacterial dual-layered polymeric membrane was fabricated by coating a top layer of graphene oxide and a sulfonated polyanion co-doped hydrogel thin film (GO-SPHF) on a bottom membrane substrate. After a two-step spin-coating of casting solutions on glass plates, dual-layered membranes were obtained by a liquid-liquid phase inversion method. The GO-SPHF composite polyethersulfone (PES) membranes (PES/GO-SPHF) showed top layers with obviously large porous structures. The chemical composition tests indicated that there were abundant hydrophilic groups enriched on the membrane surface. The examination of membrane mechanical properties indicated that the composite membranes exhibited only slightly decreased performance compared to pristine PES membranes. Moreover, to validate the potential applications of this novel dual-layered membrane in diverse fields, we tested the hemocompatibility and antibacterial activity of the membranes, respectively. Notably, the PES/GO-SPHF membranes showed highly improved in vitro hemocompatibility, such as good anti-coagulant activity, suppressed platelet adhesion and activation, low inflammation potential, and good red blood cell compatibility. Furthermore, the dual-layered membranes exhibited robust antibacterial ability after in situ loading of Ag-nanoparticles with excellent bactericidal capability to both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Due to the integration of the porous membrane structure, good mechanical strength, excellent hemocompatibility, as well as robust bactericidal capability, the GO and sulfonated polyanion co-doped dual-layered membranes may open up a new protocol to greatly demonstrate the potential application of polymeric membranes for clinical hemodialysis and many other biomedical therapies.