T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

Long-term passaging of pseudo-typed SARS-CoV-2 reveals the breadth of monoclonal and bispecific antibody cocktails.

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

[Clinical observation of accordion technique in promoting bone transport and prolonging newborn bone mineralization].

OBJECTIVE: To analyze effect of accordion technique on bone mineralization of extended bone segment in treating tibial bone defect with bone transport. METHODS: From May 2017 to October 2019, 22 patients with tibial bone defects were treated with Ilizarov bone-transport technique, and divided into two groups after bone-transport was completed, 11 patients in each group. In observation group, there were 9 males and 2 females aged from 20 to 60 years old with an average of (42.6± 13.3) years old;the length of bone defect ranged from 3 to 13 cm with an average of(6.4±2.6) cm;2 patients were suffered from upper tibial bone defects, 3 patients were middle and 6 patients were lower;patients were treated with accordion technique for 35 days. In control group, there were 10 males and 1 female aged from 41 to 60 years old with an average of (51.6±6.4) years old;the length of bone defect ranged from 3 to 10.7 cm with an average of (6.6±2.5) cm;1 patient was suffered from upper tibial bone defects, 3 patients were middle and 7 patients were lower;patients were treated with lock external fixator to waiting bone mineralization. The content of hydroxyapatite (HAP) extended bone segment was measured after bone-transport completed immediately, 35, 65 and 95 days after bone-transport was completed, respectively, then the mineralization time and healing time were compared between two groups, and the therapeutic effect of bone defect was evaluated by using Paley scoring criteria. RESULTS: Twenty-two patients were followed up from 18 to 36 months with an average of (27.0±6.3) months. The wounds on the bone defects healed spontaneously during bone transport, and there were no wound complications such as skin infection or skin necrosis occurred. There were statisticaldifference in the content of HAP of the extended bone segments at 35, 65 and 95 days after bone-transport between two groups (P<0.05). There were difference in mineralization time and healing time between two groups (P<0.05). According to Paley standard evaluation, 10 patients got excellent results, and 1 good in observation group; while 9 patients got excellent results, 2 good in control group;and there was no differences between two groups (Z=-0.607, P= 0.544). CONCLUSION: Accordion technique and locking external fixator mineralization in prolonging bone segment healing after bone-transport have the equal clinical effect, while the accordion technique could significantly accelerate the growth rate of HAP and shorten the mineralization time and healing time.

Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles.

The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 µg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.