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Single-atom nanozymes (SAzyme) have shown great promise in the area of anti-tumor therapy due to their ultra-high atom utilization efficiency. However, the therapeutic effect is far from satisfactory because of cunning cancer cell's self-protective autophagy. Herein, to solve this dilemma, we design a large-pore mesoporous Fe SAzyme loaded with macromolecular melittin pro-peptide to form Fe SAzyme@melittin pro-peptide (FePM) nanobee. When the FePM enter cells through endocytosis and are entrapped in endo/lysosomes, Fe SAzyme with glutathione oxidase (GSHOx), peroxidase (POD) and oxidase (OXD) mimicking activities can trigger collaborative CDT and ferroptosis by provoking a GSH depletion-enhanced ROS storm. Additionally, the strong absorption ability in the near-infrared II region endows Fe SAzyme with excellent PTT performance (42.1%). More importantly, the non-toxic melittin pro-peptide can be activated to membrane-lytic active melittin by overexpressed legumain in the lysosomes of cancer cells. Activated melittin then disrupts lysosomes, in this case inhibiting autophagy by reducing the formation of autolysosomes. Therefore, FePM nanobee can effectively damage cytoplasmic components to induce cancer cells death by synergistic ferroptosis, CDT and PTT. This study sheds light on the first example of large-pore mesoporous SAzyme for autophagy inhibition-enhanced multimodal synergistic antitumor therapy. [Display omitted] • A novel single-atom nanozymes (SAzyme) with Fe-N 5 coordination structure was precisely synthesized. • Large-pore mesoporous Fe SAzyme was used as a vehicle for the loading of macromolecular protein drugs firstly. • Fe SAzyme@melittin pro-peptide was specifically activated by legumain in tumor cells. • Fe SAzyme@melittin pro-peptide can achieve autophagy inhibition-enhanced antitumor synergistic ferroptosis, CDT and PTT. [ABSTRACT FROM AUTHOR]

Presents information on a study which discussed research on the use of bispecific antibody (BsAb) for cancer immunotherapy. Development of BsAb; Description of the knobs into holes mutation; Selection of tumor-specific antigens in cancer treatment; Anti-tumor effects mediated by anti-CD3/anti-tumor BsAb in vitro and in vivo.

One of the major mechanisms of multidrug resistance (MDR) in cancer therapy is the overexpression of P-glycoprotein (Pgp). We previously reported that pyronaridine (PND), a synthetic quinoline derivative in the clinic for the treatment of malaria infections, was capable of reversing MDR phenotype in Pgp-overexpressing tumor cells. Here we further evaluated the reversal activity of PND using two Pgp-overexpressing human tumor cell lines: K562/A02 and MCF-7/ADR. PND significantly enhanced the sensitivity of K562/A02 and MCF-7/ADR cells to doxorubicin (DOX), but had no such effect on the parent K562 and MCF-7 cells. The MDR-modulating effect of PND persisted for longer than 24 h after removal of the agent from the culture. In nude mice bearing K562/A02 xenografts PND significantly enhanced the antitumor activity of DOX when given intraperitoneally or orally without increasing the toxicity of DOX. Our observations suggest that PND represents a promising agent for overcoming MDR in cancer therapy. [Copyright &y& Elsevier]

Monoclonal antibodies (mAb) directed against CD20, either unmodified or in radiolabeled forms, have been successfully used in clinic as effective therapeutic agents in the management of non-Hodgkin''s B-cell lymphoma. Despite all clinical success the exact mechanisms of action of various anti-CD20 antibodies remains mostly unclear. Several mechanisms have been proposed to be responsible for the therapeutic activity of anti-CD20 antibodies, including antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, and direct inhibition of tumor growth via induction of apoptosis. We previously produced an anti-CD20 mAb, HI47, and showed that the antibody effectively blocked human B-cell proliferation in vitro and inhibited xenografted B-cell lymphoma in nude mice. In this study, we engineered the chimeric versions of both the Fab and F(ab)′2 fragments of HI47 and produced the fragments in E. coli. Both fragments competed efficiently with HI47 for binding to CD20+ B cells, and inhibited proliferation of B-lymphoma cells in a dose-dependent manner. Mechanistic studies revealed that both antibody fragments induced significant degree of B-cell apoptosis that is independent of any cross-linking agents. Further, both the F(ab)′2 and Fab fragments when administered in vivo significantly inhibited the growth of human B-cell lymphoma xenografts in nude mice. The bivalent F(ab)′2 fragment showed consistently better efficacy compared to its monovalent Fab counterpart in inducing apoptosis and inhibiting B-cell lymphoma growth both in vitro and in vivo. Taken together, these observations suggest that HI47 and its fragments most likely exert their antitumor activity through induction of cell apoptosis, and cross-linking/dimerization of CD20 molecules on B- cell surface is an important, but not essential, process for therapeutic efficacy of HI47 and its fragments. [Copyright &y& Elsevier]

Bispecific antibodies have been exploited both as cancer immunodiagnostics and as cancer therapeutics, and have shown promise in several clinical trials in cancer imaging and therapy. A number of bispecific antibodies against B-cell markers have been shown to be effective in vitro in mediating tumor cell lysis and in vivo in inhibiting tumor growth in animal models. We have constructed a bispecific diabody from the variable genes encoding two hybridoma-derived monoclonal antibodies directed against human CD20 on B cells and CD3 on T cells. The anti-CD20×anti-CD3 diabody was expressed in a single Escherichia coli host and purified by a one-step affinity chromatography. The bispecific diabody bound as efficiently to both CD20- and CD3-positive cells as the respective parental antibodies, and was capable of cross-linking CD20-positive tumor cells and human T lymphocytes as shown by cellular rosetting. The diabody effectively lysed human B-lymphoma cells in the presence of T-enriched human peripheral blood lymphocytes (PBL). Further, when combined with human PBL and interleukin-2, the diabody significantly prolonged the survival of nude mice inoculated with human B-lymphoma cells. Taken together, our results suggest that an anti-CD20×anti-CD3 diabody may have significant clinical application in the treatment of human CD20-positive B-cell malignancies. [Copyright &y& Elsevier]