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Background: Multiple myeloma (MM) has become the second most hematological malignance. The patients are rarely cured and experience the recurrence or resistance. There is still an urgent need to develop potential therapeutic agents with better response. BCMA (B cell maturation antigen) and GPRC5D (G-protein-coupled receptor class 5 member D) are independently expressed in MM cells. The percentage of MM patients with single or co-expression of BCMA and GPRC5D is close to 90%, which means both are the ideal therapeutical targets. Methods/Results: Anti-GPRC5D and anti-BCMA antibodies with high binding affinity were respectively screened from hybridoma or alpaca phage library. Two antibodies were assembled to anti-CD3 antibody with low binding activity. Candidate molecule SCR-8572 was selected from dozens of triple-specific antibodies. The affinity of SCR-8572 to recombinant BCMA protein is 41.3pM. Binding EC50 to GPRC5D over-expressed cell is 2.4nM. SCR-8572 also showed very good binding activity with several MM cell lines, such as H929, RPMI-8226 and Molp-8, etc. The weak binding to CD3 can decrease the sink effect in peripheral blood. In vitro cytotoxicity of SCR-8572 against three MM cell lines with different expression levels was evaluated. It showed strong tumor-induced T cell activation but not non-specific activation, which resulted in the excellent tumor cytotoxicity. And the cytotoxicity was much stronger than that of BCMA-CD3 (Teclistamab analogue) and/or GPRC5D-CD3 (Talquetamab analogue) treatments. In the meanwhile, the cytokine release levels of IL-6 and TNFa are acceptable and similar with two TCE benchmarks. This predicted the low risk of CRS. We also conducted in vivo efficacy test in two MM Cell-derived-Xenograft mice models with PBMC reconstitution. SCR-8572 can eliminate the tumors and maintained tumor regression after drug withdrawal, while the tumor relapse occurred in Teclistamab and/or Talquetamb groups. The preliminary toxic effect of SCR-8572 was explored in cynomolgus by 10mpk followed by 30mpk intravenous injection with 21 days interval. The cynomolgus tolerated very well. Lymphocyte reduction was observed which indicated the lymphocyte redistribution. C Reaction Protein (CRP) level increased to 19-33mg/L and recovered to baseline in 7 days. IL-6 level increased to 116.3pg/ml in 24 hours after 10mpk injection and 52.5pg/ml in 2 hours after followed 30mpk injection. IFNγ, IL-2 and IL-10 levels were detected to be very low or below the limit of quantitation. Conclusion: We have developed a novel dual-targeted T cell engager for MM treatment, which showed strong tumor killing effect in in vitro and in vivo models with low CRS risk. The toleration of high dosage in cynomolgus suggested the good safety performance. Above all, the preclinical study illustrated SCR-8572 can be a promising therapeutic candidate in treatment of MM patients. Citation Format: Yayuan Fu, Shumei You, Menghao Wei, Bowei Yin, Qi Deng, Xiaokang Qin, Yun Zhang, Yanqiu Wang, Renhong Tang. A novel T cell engager targeting BCMA and GPRC5D showed promising preclinical activity with low toxic risk for multiple myeloma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1883.

Sphingomonas carotinifaciens strain L9-754T (DSM 27347) is a gram-negative, chemoheterotrophic, and rod-shaped endophyte isolated from the stem tissues of Jatropha curcas L. This strain has putative in vitro antagonistic ability against the plant pathogenic fungus Magnaporthe grisea. A draft genome of L9-754T was obtained using the PacBio SMRT cell platform. By analyzing the genome of strain L9-754T, a gene cluster (GQR91_18700 - GQR91_18715) related to an antioxidant enzyme was identified in the obtained draft genome. The information obtained from the draft genome is expected to reveal the putative properties helpful in biocontrol applications.

Objectives Achromobacter spanius is a newly described, non-fermenting, Gram-negative, coccoid pathogen isolated from human blood. Whole-genome sequencing of the A. spanius type strain was performed to investigate the mechanism of pathogenesis of this strain at a genomic level. Methods The complete genome of A. spanius type strain DSM 23806T was sequenced using single-molecule real-time (SMRT) DNA sequencing. Results The complete genome of DSM 23806T consists of one circular DNA chromosome of 6 425 783 bp with a G + C content of 64.26%. The entire genome contains 5804 predicted coding sequences (CDS) and 55 tRNAs. Genomic island (GI) analysis showed that this strain encodes several important pathogenesis- and resistance-related genes. Conclusions These results strongly suggest that GIs provide some fitness advantages in A. spanius type strain DSM 23806T. This report provides an extensive understanding of A. spanius at a genomic level as well as an understanding of the evolution of A. spanius.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the leading swine pathogens and causes major economic loss to the global swine industry. In this study, a total of 49 PRRSV isolates were collected from different swine herds in seven provinces in Southeast China from 2014 to 2015. All the ORF5 genes and some Nsp2 genes were sequenced. Phylogenetic analysis showed that all the isolates belonged to the North America genotype. Among them, five isolates formed a new subgenotype IV derived from highly pathogenic PRRSV (HP-PRRSV). Six isolates formed subgenotype III, which were closely related to the NADC30 strain in the US. These isolates formed 13 putative N-linked glycosylation site (NGS) patterns based on N30, 33, 34, 35, 44 and 51. There were fewer NGSs of isolates in subgenotype IV than in subgenotype III. This indicates that the two new subgenotypes of PRRSV strains with different NGS patterns were spreading in those regions of China. The genetic diversity should be considered for the control and prevention of this disease.

Achromobacter spanius is a newly described, non-fermenting, Gram-negative, coccoid pathogen isolated from human blood. Whole-genome sequencing of the A. spanius type strain was performed to investigate the mechanism of pathogenesis of this strain at a genomic level.The complete genome of A. spanius type strain DSM 23806The complete genome of DSM 23806These results strongly suggest that GIs provide some fitness advantages in A. spanius type strain DSM 23806

Achromobacter insolitus is a newly described, Gram-negative, small (1-2 mm long) and coccoid pathogen that has been isolated from leg wound. Due to its potential threat to human beings, the type strain of this species LMG 6003T was completely sequenced in this study. The genomic analysis revealed that the genome of LMG 6003T consists of one circular DNA chromosome of 6 492 697 bp with a GC content of 65.10%. The entire genome contains 6208 predicted coding genes, 61 tRNAs and 13 rRNA genes. Comparative genome analysis between LMG 6003T and another selected 10 sequenced Achromobacter revealed that 725 genes only exist in LMG 6003T. In particular, these genes include several important pathogenic-related genes such as Type IV prepilin peptidase (TadV/CpaA), Type VI secretion lipoprotein (VasD) and type 1 fimbriae major subunit (FimA). Genomic island (GI) analysis also suggests the existence of GIs in LMG 6003T. All these results strongly suggest the unique genomic features in LMG 6003T against other Achromobacter species. This report will provide us with an extended understanding of A. insolitus at the genomic level and would be helpful for understanding the evolution of the Achromobacter genus.