Natural selection and recombination at host-interacting lipoprotein loci drive genome diversification of Lyme disease and related bacteria.

Lyme disease, caused by spirochetes in the Borrelia burgdorferi sensu lato clade within the Borrelia genus, is transmitted by Ixodes ticks and is currently the most prevalent and rapidly expanding tick-borne disease in Europe and North America. We report complete genome sequences of 47 isolates that encompass all established species in this clade while highlighting the diversity of the widespread human pathogenic species B. burgdorferi. A similar set of plasmids has been maintained throughout Borrelia divergence, indicating that they are a key adaptive feature of this genus. Phylogenetic reconstruction of all sequenced Borrelia genomes revealed the original divergence of Eurasian and North American lineages and subsequent dispersals that introduced B. garinii, B. bavariensis, B. lusitaniae, B. valaisiana, and B. afzelii from East Asia to Europe and B. burgdorferi and B. finlandensis from North America to Europe. Molecular phylogenies of the universally present core replicons (chromosome and cp26 and lp54 plasmids) are highly consistent, revealing a strong clonal structure. Nonetheless, numerous inconsistencies between the genome and gene phylogenies indicate species dispersal, genetic exchanges, and rapid sequence evolution at plasmid-borne loci, including key host-interacting lipoprotein genes. While localized recombination occurs uniformly on the main chromosome at a rate comparable to mutation, lipoprotein-encoding loci are recombination hotspots on the plasmids, suggesting adaptive maintenance of recombinant alleles at loci directly interacting with the host. We conclude that within- and between-species recombination facilitates adaptive sequence evolution of host-interacting lipoprotein loci and contributes to human virulence despite a genome-wide clonal structure of its natural populations. IMPORTANCE: Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus Borrelia, transmitted by hard-bodied Ixodes ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe. Borrelia interspecies and intraspecies genome comparisons of Lyme disease-related bacteria are essential to reconstruct their evolutionary origins, track epidemiological spread, identify molecular mechanisms of human pathogenicity, and design molecular and ecological approaches to disease prevention, diagnosis, and treatment. These Lyme disease-associated bacteria harbor complex genomes that encode many genes that do not have homologs in other organisms and are distributed across multiple linear and circular plasmids. The functional significance of most of the plasmid-borne genes and the multipartite genome organization itself remains unknown. Here we sequenced, assembled, and analyzed whole genomes of 47 Borrelia isolates from around the world, including multiple isolates of the human pathogenic species. Our analysis elucidates the evolutionary origins, historical migration, and sources of genomic variability of these clinically important pathogens. We have developed web-based software tools (BorreliaBase.org) to facilitate dissemination and continued comparative analysis of Borrelia genomes to identify determinants of human pathogenicity.

A wide distribution of Beiji nairoviruses and related viruses in Ixodes ticks in Japan.

Beiji nairovirus (BJNV), in the family Nairoviridae, the order Bunyavirales, was recently reported as a causative agent of an emerging tick-borne zoonotic infection in China. This study investigated the prevalence of BJNV in ticks in Japan. Screening of over 2,000 ticks from multiple regions revealed a widespread distribution of BJNV and BJNV-related viruses in Japan, particularly in the northern island, and in other high altitude areas with exclusive occurrence of Ixodes ticks. Phylogenetic analysis identified three distinct groups of nairoviruses in ticks in Japan: BJNV, Yichun nairovirus (YCNV) and a newly identified Mikuni nairovirus (MKNV). BJNV and YCNV variants identified in ticks in Japan exhibited high nucleotide sequence identities to those in China and Russia with evidence of non-monophyletic evolution among BJNVs, suggesting multiple cross-border transmission events of BJNV between the Eurasian continent and Japan. Whole genome sequencing of BJNV and MKNV revealed a unique GA-rich region in the S segment, the significance of which remains to be determined. In conclusion, the present study has shown a wide distribution and diversity of BJNV-related nairoviruses in Ixodes ticks in Japan and has identified unique genomic structures. The findings demonstrate the significance of BJNV as well as related viruses in Japan and highlight the necessity of monitoring emerging nairovirus infections and their potential risks to public health.

Verification of surgical factors affecting the efficiency of stone extraction with one-surgeon basketing technique using a f-URSL simulation model.

PURPOSE: Stone extraction is an important treatment option when performing flexible ureteroscopic lithotripsy (f-URSL) for upper urinary stones. We used a f-URSL simulator model to investigate surgical factors affecting the efficacy of stone extraction with the one-surgeon basketing technique. MATERIALS AND METHODS: This simulator-based study involved eight urologists and eight residents. These participants each performed two tasks, with Flexor (Cook Medical) and Navigator (Boston Scientific) ureteral access sheaths, with and without the M-arm (MC Medical) single-use basket holder, and with models representing both left and right kidneys. The two tasks were to touch each renal calix with the ureteroscope, and to extract stones. As outcomes, we recorded the number of times that the ureteroscope became stuck during insertion, the number of times a stone was dropped during removal, the number of times the basket forceps were opened and closed, and the time required to accomplish each task. RESULTS: The ureteroscope became stuck significantly more often when Navigator was used compared with Flexor overall, and for both urologists and residents (all p<0.01). Stones were dropped significantly more often on the ipsilateral side (kidney on the same side as the operator's hand) than on the contralateral side overall (p=0.01), and the basket forceps were opened and closed significantly more often on the ipsilateral side than on the contralateral side both overall and by residents (all p<0.01). CONCLUSIONS: The efficiency of stone extraction during f-URSL with the one-surgeon basketing technique was affected by differences in ureteral access sheath and the kidney side.

Unprecedented genetic variability of PFam54 paralogs among Eurasian Lyme borreliosis-causing spirochetes.

Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere caused by spirochetes belonging to the Borrelia burgdorferi sensu lato (Bbsl) complex. Borrelia spirochetes circulate in obligatory transmission cycles between tick vectors and different vertebrate hosts. To successfully complete this complex transmission cycle, Bbsl encodes for an arsenal of proteins including the PFam54 protein family with known, or proposed, influences to reservoir host and/or vector adaptation. Even so, only fragmentary information is available regarding the naturally occurring level of variation in the PFam54 gene array especially in relation to Eurasian-distributed species. Utilizing whole genome data from isolates (n = 141) originated from three major LB-causing Borrelia species across Eurasia (B. afzelii, B. bavariensis, and B. garinii), we aimed to characterize the diversity of the PFam54 gene array in these isolates to facilitate understanding the evolution of PFam54 paralogs on an intra- and interspecies level. We found an extraordinarily high level of variation in the PFam54 gene array with 39 PFam54 paralogs belonging to 23 orthologous groups including five novel paralogs. Even so, the gene array appears to have remained fairly stable over the evolutionary history of the studied Borrelia species. Interestingly, genes outside Clade IV, which contains genes encoding for proteins associated with Borrelia pathogenesis, more frequently displayed signatures of diversifying selection between clades that differ in hypothesized vector or host species. This could suggest that non-Clade IV paralogs play a more important role in host and/or vector adaptation than previously expected, which would require future lab-based studies to validate.

Poor performance status is a risk factor for higher detection of Gram positive coccus in stone-related pyelonephritis.

INTRODUCTION: We aimed to investigate the detection rate of causative organisms in stone-related pyelonephritis and to compare their distribution according to patient backgrounds. METHODS: We retrospectively identified patients with stone-related pyelonephritis. Clinical data were collected between November 2012 and August 2020 at Wakayama Medical University Hospital, including on patient backgrounds and causative organisms. Patients were categorized by Eastern Cooperative Oncology Group performance status (PS) as the good PS group (0, 1) and the poor PS group (2-4). Bacteria were divided into Gram-positive cocci (GPC) or non-GPC groups and logistic regression analysis was used to examine factors that predict detection of GPC. RESULTS: Seventy-nine patients had stone-related pyelonephritis, 54 (68.4 %) in the good PS group and 25 (31.6 %) in the poor PS group. In the good PS group, Escherichia coli (67 %) was followed by Klebsiella species (9 %), while in the poor PS group, Escherichia coli (20 %) was followed by Enterococci and Staphylococci (12 %). GPC detection rate was significantly higher in the poor PS group than in the good PS group (40.0 % vs 14.8 %, p = 0.016), and multivariate logistic regression analysis showed that poor PS was an independent factor predicting detection of GPC (OR = 6.54, p = 0.02). CONCLUSIONS: The distribution of the causative organisms in stone pyelonephritis was similar to that in common complicated urinary tract infections. Poor PS may be an independent predictor of GPC detection in patients with stone pyelonephritis.

Three cases of open surgical procedures on ileal conduits for the repair of benign ureteroenteric anastomotic strictures after total pelvic exenteration of rectal tumors.

Ureteroenteric anastomotic strictures (UEAS) are typical complications after creating an ileal conduit for total pelvic exenteration (TPE) of rectal tumors. We report the ileal conduit for reconstruction in three patients, in the age-range of 47-73 years. Case 1 was when a left-sided UEAS had sufficient length of ureter for anastomosis, Case 2 was a right-sided UEAS with sufficient length of ureter for anastomosis, and Case 3 was a left-sided UEAS with insufficient length of ureter for anastomosis. There were no complications after operation and no recurrence of UEAS. It is important to learn the open surgical procedures for repair of a benign UEAS after TPE of rectal cancers. This has fewer complications and is safe in the long term.

How many times can patients tolerate reoperation for the local recurrence of colorectal cancer in terms of complications?

The frequency of resection for the recurrence of colorectal cancer has not been investigated in previous studies. Likewise, the related postoperative complications and the limit for indicating surgical resection has not been reported. Herein, we reported the complications of a highly frequent surgical approach for rectal cancer recurrence, i.e., exceeding three reoperations, based on our clinical experience. We included 15 cases exceeding two operations for the local recurrence of colorectal cancer from 2014 to 2019. We examined the postoperative complications classified as Clavien?Dindo IIIb. The positive rates of the complications were 0 (0.0%), 0 (0.0%), 2 (13.3%), 3 (37.5%), and 0 (0.0%) for the primary, 1st recurrent, 2nd recurrent, 3rd recurrent, and 4th recurrent operation group (p=0.027), respectively. It is important to exercise caution in handling cases exceeding two reoperations (exceeding three reoperations including the primary operation). J. Med. Invest. 70 : 369-376, August, 2023.

Candidatus Lariskella arthopodarum endosymbiont is the main factor differentiating the microbiome communities of female and male Borrelia-positive Ixodes persulcatus ticks.

Ixodes persulcatus, a hard-bodied tick species primarily found in Asia and Eastern Europe, is a vector of pathogens to human and livestock hosts. Little research has been done on the microbiome of this species, especially using individual non-pooled samples and comparing different geographical locations. Here, we use 16S rRNA amplicon sequencing to determine the individual microbial composition of 85 Borrelia-positive I. persulcatus from the Japanese islands of Hokkaido and Honshu. The resulting data (164 unique OTUs) were further analyzed to compare the makeup and diversity of the microbiome by sex and location, as well as to determine the presence of human pathogens. We found that, while location had little influence, the diversity of I. persulcatus microbiome was predominantly dependent on sex. Males were seen to have higher microbiome diversity than females, likely due to the high presence of endosymbiotic Candidatus Lariskella arthropodarum within the female microbial communities. Furthermore, high read counts for five genera containing potentially human pathogenic species were detected among both male and female microbiomes: Ehrlichia, Borrelia, Rickettsia, Candidatus Neoehrlichia and Burkholderia and co-infections between different pathogens were frequent. We conclude that the microbiome of I. persulcatus depends mainly on sex and not geographical location and that the major difference between sexes is due to the high abundance of Ca. L. arthropodarum in females. We also stress the importance of this tick species as a vector of potential human pathogens frequently found in co-infections.

Genome Sequence of a Clinical Isolate of the Human Pathogenic Strain "Candidatus Borrelia fainii" Qtaro.

We report sequences of the complete linear chromosome and five linear plasmids of the relapsing fever spirochete "Candidatus Borrelia fainii" Qtaro. The chromosome sequence of 951,861 bp and the 243,291 bp of plasmid sequences were predicted to contain 852 and 239 protein-coding genes, respectively. The predicted total GC content was 28.4%.

Co-infection of tick-borne bacterial pathogens in ticks in Inner Mongolia, China.

Tick-borne infectious diseases pose a serious health threat in certain regions of the world. Emerging infectious diseases caused by novel tick-borne pathogens have been reported that are causing particular concern. Several tick-borne diseases often coexist in the same foci, and a single vector tick can transmit two or more pathogens at the same time, which greatly increases the probability of co-infection in host animals and humans and can lead to an epidemic of tick-borne disease. The lack of epidemiological data and information on the specific clinical symptoms related to co-infection with tick-borne pathogens means that it is not currently possible to accurately and rapidly distinguish between a single pathogen infection and co-infection with multiple pathogens, which can have serious consequences. Inner Mongolia in the north of China is endemic for tick-borne infectious diseases, especially in the eastern forest region. Previous studies have found that more than 10% of co-infections were in host-seeking ticks. However, the lack of data on the specific types of co-infection with pathogens makes clinical treatment difficult. In our study, we present data on the co-infection types and the differences in co-infection among different ecological regions through genetic analysis of tick samples collected throughout Inner Mongolia. Our findings may aid clinicians in the diagnosis of concomitant tick-borne infectious diseases.

Clinical significance of serum autoantibodies in patients with sarcoidosis.

BACKGROUND: The association between sarcoidosis and autoimmunity has been reported for years. However, the significance of autoantibodies in the pathophysiology and clinical management of sarcoidosis is not well understood. No autoantibodies that can be used as serologic biomarkers to diagnose the disease, monitor the state of the disease, and predict the prognosis of patients are established. METHODS: We performed a comprehensive analysis of serum autoantibodies and analyzed their associations with clinical features of sarcoidosis. RESULTS: Patients with systemic autoimmune rheumatic diseases-associated autoantibodies had a higher prevalence of advanced radiographic stage and consolidations in high-resolution computed tomography than patients without autoantibodies (p < .05). Age, sex, clinical history, pulmonary function tests, serum angiotensin-converting enzyme levels, rheumatoid factor, and the number of involved organs were not significantly different between the two groups. CONCLUSIONS: There may be an association between autoantibodies and more advanced pulmonary lesions in patients with sarcoidosis. Further investigations are needed to establish the significance of autoantibodies.

Detection of Old and New World Relapsing Fever Borreliae in Ornithodoros Ticks Collected from Warthog Burrows in Zambia.

Relapsing fever (RF) is an arthropod-borne disease caused by Borrelia spirochete, which is one of the major public health concerns in endemic regions including Africa. However, information on Borrelia spirochetes is limited in Zambia. Here, we investigate the Borrelia spirochetes harbored by Ornithodoros ticks in Zambian National Parks. We analyzed 182 DNA samples pooled from 886 Ornithodoros ticks. Of these, 43 tested positive, and their sequence revealed that the ticks harbored both Old and New World RF borreliae. This research presents the first evidence of Old-World RF borreliae in Zambia. The New World RF borreliae detected herein differed from the Candidatus Borrelia fainii previously reported in Zambia and were closely related to the pathogenic Borrelia sp. VS4 identified in Tanzania. Additionally, Borrelia theileri was recently reported in Zambia. Hence, at least four different Borrelia species occur in Zambia, and the organisms causing relapsing fever there might be more complex than previously thought. We empirically confirmed that real-time PCR with TaqMan minor groove binder probes accurately and simultaneously detected both Old and New World RF. In this manner, they could facilitate quantitative analyses of both types of RF borreliae. Subsequent investigations should endeavor to isolate the aforementioned Borrelia spp. and perform serosurveys on patients with RF.

Strain accumulation and release associated with the occurrence of SSEs in the subduction zones of the Japanese Islands.

We investigated the spatiotemporal changes in strain associated with the occurrence of slow slip events (SSEs) in the subduction zones of the Japanese Islands and compared the spatial distribution of both the amount of strain accumulated for the period before and during the SSEs release using time series data from the Global Navigation Satellite System (GNSS). In this study, four SSEs were analysed: the Tokai long-term SSE (2000-2005), the Boso-Oki short-term SSE (2007), and the Bungo Channel long-term SSEs (2009-2011 and 2018-2019). As a result, we found strong negative correlations for all four dilatations before and during SSE occurrence. For these dilatations, we estimated the amount of strain released at the time of occurrence of the SSE relative to that accumulated during the period prior to the SSE. The result indicates that not all the accumulated strain before the SSEs was released when the SSEs occurred. Moreover, it is highly likely that the strain released by SSE is not only due to the strain accumulation just below the SSE occurrence region, but also due to the strain accumulation on the shallower plate boundary, which is a seismogenic zone for a future megathrust earthquake.

Out of Asia? Expansion of Eurasian Lyme borreliosis causing genospecies display unique evolutionary trajectories.

Vector-borne pathogens exist in obligate transmission cycles between vector and reservoir host species. Host and vector shifts can lead to geographic expansion of infectious agents and the emergence of new diseases in susceptible individuals. Three bacterial genospecies (Borrelia afzelii, Borrelia bavariensis, and Borrelia garinii) predominantly utilize two distinct tick species as vectors in Asia (Ixodes persulcatus) and Europe (Ixodes ricinus). Through these vectors, the bacteria can infect various vertebrate groups (e.g., rodents, birds) including humans where they cause Lyme borreliosis, the most common vector-borne disease in the Northern hemisphere. Yet, how and in which order the three Borrelia genospecies colonized each continent remains unclear including the evolutionary consequences of this geographic expansion. Here, by reconstructing the evolutionary history of 142 Eurasian isolates, we found evidence that the ancestors of each of the three genospecies probably have an Asian origin. Even so, each genospecies studied displayed a unique substructuring and evolutionary response to the colonization of Europe. The pattern of allele sharing between continents is consistent with the dispersal rate of the respective vertebrate hosts, supporting the concept that adaptation of Borrelia genospecies to the host is important for pathogen dispersal. Our results highlight that Eurasian Lyme borreliosis agents are all capable of geographic expansion with host association influencing their dispersal; further displaying the importance of host and vector association to the geographic expansion of vector-borne pathogens and potentially conditioning their capacity as emergent pathogens.

Serologic Evidence of Human Exposure to Ehrlichiosis Agents in Japan.

In retrospective analyses, we report 3 febrile patients in Japan who had seroconversion to antibodies against Ehrlichia chaffeensis antigens detected by using an immunofluorescence and Western blot. Our results provide evidence of autochthonous human ehrlichiosis cases and indicate ehrlichiosis should be considered a potential cause of febrile illness in Japan.

Co-infections with multiple pathogens in natural populations of Ixodes persulcatus ticks in Mongolia.

BACKGROUND: In Mongolia, the taiga tick Ixodes persulcatus is the major vector of tick-borne pathogens. Knowledge about co-infections of these pathogens in ticks is necessary both for understanding their persistence in nature and for diagnosing and treating tick-borne diseases. METHODS: The prevalence of seven tick-borne infections in 346 I. persulcatus collected from the Selenge and Bulgan provinces of Mongolia was evaluated using real-time PCR. Quantification of Borrelia spp. was performed using multiplex quantitative PCR targeting the 16S rRNA gene. Genetic analysis of Borrelia spp. in 11 ticks infected with Borrelia miyamotoi, including six ticks co-infected with Borrelia burgdorferi sensu lato (s.l.), was performed by high-throughput sequencing of the flaB gene fragment. RESULTS: Six ticks (1.7%) were infected with tick-borne encephalitis virus (TBEV); 171 (49.4%), with B. burgdorferi sensu lato; 17 (4.9%), with B. miyamotoi; 47 (13.6%), with Anaplasma phagocytophilum; and 56 (16.2%), with Ehrlichia sp. Neither Rickettsia sibirica nor R. heilongjiangensis were detected. Borrelia burgdorferi s.l. occurred as co-infection in 55 (32.2%) of all infected ticks. The other pathogens co-infected ticks in 58.8-70.2% of cases. No pairwise associations between co-infecting pathogens were observed, with the exception of a positive association between A. phagocytophilum and Ehrlichia sp. INFECTIONS: The spirochete loads of B. miyamotoi were significantly higher than those of B. burgdorferi s.l. (mean: 5.2 vs 4.0 log10 genome copies/tick, respectively). Ten isolates of B. miyamotoi belonged to the Siberian lineage. Borrelia burgdorferi s.l was represented by nine isolates of B. afzelii, B. bavariensis and B. garinii. CONCLUSIONS: In populations of I. persulcatus inhabiting the Selenge and Bulgan provinces of Mongolia, five vector-borne pathogens, i.e. TBEV, B. burgdorferi s.l., B. miyamotoi, A. phagocytophilum and Ehrlichia sp., persist independently from each other, with the exception of A. phagocytophilum and Ehrlichia sp. which seem to share the circulation mode. The discrepancies in B. burgdorferi s.l. and B. miyamotoi prevalence and spirochete load per tick suggest that different ecological niches are occupied by Lyme disease and relapsing fever agents. High-throughput sequencing allows genetic identification of borreliae species in co-infected ticks.

Autopsy case of a patient with rapidly progressive combined small-cell lung carcinoma with spindle-shaped cell tumor.

A 69-year-old Japanese man visited our hospital because of worsening shortness of breath. His chest computed tomography (CT) showed a giant left lung mass with a massive left pleural effusion. He could not be treated with chemotherapy and eventually died from a rapidly progressive tumor. He was diagnosed with combined small cell lung carcinoma (C-SCLC) with spindle-shaped cell tumor at autopsy. C-SCLC is characterized by pathologically concurrent SCLC and adenocarcinoma or squamous cell carcinoma, or rarely, spindle-shaped cell tumor. The clinical course of C-SCLC with spindle-shaped cell tumor has not previously been determined. Our patient's tumor increased by 2.59-fold in 20 days. The combination of C-SCLC with spindle-shaped cell tumor suggested rapid progression and a poor prognosis.

Novel symbionts and potential human pathogens excavated from argasid tick microbiomes that are shaped by dual or single symbiosis.

Research on vector-associated microbiomes has been expanding due to increasing emergence of vector-borne pathogens and awareness of the importance of symbionts in the vector physiology. However, little is known about microbiomes of argasid (or soft-bodied) ticks due to limited access to specimens. We collected four argasid species (Argas japonicus, Carios vespertilionis, Ornithodoros capensis, and Ornithodoros sawaii) from the nests or burrows of their vertebrate hosts. One laboratory-reared argasid species (Ornithodoros moubata) was also included. Attempts were then made to isolate and characterize potential symbionts/pathogens using arthropod cell lines. Microbial community structure was distinct for each tick species. Coxiella was detected as the predominant symbiont in four tick species where dual symbiosis between Coxiella and Rickettsia or Coxiella and Francisella was observed in C. vespertilionis and O. moubata, respectively. Of note, A. japonicus lacked Coxiella and instead had Occidentia massiliensis and Thiotrichales as alternative symbionts. Our study found strong correlation between tick species and life stage. We successfully isolated Oc. massiliensis and characterized potential pathogens of genera Ehrlichia and Borrelia. The results suggest that there is no consistent trend of microbiomes in relation to tick life stage that fit all tick species and that the final interpretation should be related to the balance between environmental bacterial exposure and endosymbiont ecology. Nevertheless, our findings provide insights on the ecology of tick microbiomes and basis for future investigations on the capacity of argasid ticks to carry novel pathogens with public health importance.

Suppressive effects of Ixodes persulcatus sialostatin L2 against Borrelia miyamotoi-stimulated immunity.

Borrelia miyamotoi infection is an emerging tick-borne disease that causes hard tick-borne relapsing fever. B. miyamotoi is transmitted through the bite of ticks, including Ixodes persulcatus. Although accumulating evidence suggests that tick salivary proteins enhance the infectivity of other tick-borne pathogens, the association of B. miyamotoi with tick-derived proteins remains unknown. In this study, the effect of I. persulcatus sialostatin L2 (Ip-sL2), a tick-derived cystatin, on specific immunity to B. miyamotoi was preliminarily investigated in vitro. Mice were immunized with heat-killed B. miyamotoi and in vitro analyses of the splenocytes of the immunized mice indicated that the expression levels of the activation markers of CD11c+ and CD3+ cells were significantly upregulated by B. miyamotoi stimulation. Spleen cells from B. miyamotoi-immunized mice were used to determine whether Ip-sL2 regulates murine immune responses against B. miyamotoi. Treatment with Ip-sL2 in vitro inhibited the activation of CD11c+ and CD3+ cells as well as inflammatory cytokine production by cultured splenocytes. These findings show that Ip-sL2 has modulatory effects on murine immune responses to B. miyamotoi. Therefore, it is necessary to clarify in the future whether Ip-sL2 is involved in the enhanced infectivity of B. miyamotoi.

A Defucosylated Mouse Anti-CD10 Monoclonal Antibody (31-mG2a-f) Exerts Antitumor Activity in a Mouse Xenograft Model of Renal Cell Cancers.

CD10 is a cell surface metalloendopeptidase that cleaves and degrades many secreted physiologically active peptides by its enzymatic activity. Although CD10 expression has been found in various types of cells, its expression is increased in several cancers, including renal cancer. In this study, the antitumor activity of a novel anti-human CD10 monoclonal antibody (mAb) was investigated. A defucosylated mouse IgG2a version of C10Mab-31 (31-mG2a-f) was created from an anti-CD10 mAb, C10Mab-31 (IgG1, kappa). Both C10Mab-31 and 31-mG2a-f specifically reacted with endogenous CD10 in renal cancer cells, VMRC-RCW, with the dissociation constant (KD) values of 6.3 × 10-9 M and 1.1 × 10-9 M, respectively, indicating high binding affinity. To further examine the anti-CD10 mAb-mediated effector functions, the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) were examined. The 31-mG2a-f significantly exhibited ADCC and CDC against VMRC-RCW cells in vitro. Furthermore, 31-mG2a-f exhibited antitumor activities in mouse xenografts of VMRC-RCW cells. These results suggest that 31-mG2a-f exerts antitumor activities against CD10-expressing renal cancers and could be a valuable therapeutic candidate for treating them.