Alethia Biotherapeutics (Canada)

This study proposed a novel design and personalized approach to developing an intra-vaginal device, also known as a pessary, for the treatment of Pelvic Organ Prolapse (POP). Although POP is likely to have a more diverse dynamic than other health conditions in women, it is currently treated as a "one-shape-fits-all" problem in all cases. Pessaries are conservative devices inserted into the vagina to support its internal structure and predominantly come in a ring shape design. Failure rates as high as 50% within the first year of use have been attributed to the poor design of these pessaries; with symptoms such as irritation, bleeding, and lacerations felt by most users. To address this problem, a new base shape design was proposed and its deformation was examined using Finite Element Analysis (FEA). Based on the anatomical measurements of each patient, the base design can be adjusted accordingly. To demonstrate the effectiveness of the proposed design, a comparative study was conducted with the most commonly used support pessary, also known as the ring pessary. In order to model the large deformation of the pessaries, the hyperelastic constitutive law (Yeoh model) was fitted to the available stress-strain data of SIL 30 (a silicone urethane resin supplied by Carbon Inc.). The results showed that re-directing the reaction forces of the pessary towards the lateral walls, supported by the pelvic bones, could decrease the overall displacement of the pessaries, and provide effective symptomatic relief thereby, delaying or preventing surgical procedures.Clinical relevance- There is a clear clinical need to develop a more effective conservative therapy for managing POP. The personalized pessaries proposed in this paper can be an effective method for providing symptomatic relief and avoiding displacement, compared to the currently available devices on the market. Made-to-measure for each patient, the devices are anatomically suited and can be adjusted throughout a patient's treatment plan to allow for higher compliance and overall success rate.

Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.

Abstract Starting from total RNA prepared from late-stage serous ovarian tumors and low-malignancy potential tumors, a sensitive subtractive cloning technology called STAR was used to identify differentially expressed sequences that were up-regulated in the malignant tumors. This analysis led to the identification of KAAG1, an antigen that is specifically expressed in the vast majority of the ovarian tumors. Monoclonal antibodies (mAbs) that bind to human KAAG1 were generated and one of these, AB-3A4, interacted with KAAG1 expressed on the surface of several ovarian cancer, triple-negative breast cancer (TNBC) and prostate cancer cell lines. Further studies indicated that the AB-3A4/KAAG1 complex was rapidly internalized and co-localized with LAMP1, a marker of lysosomes, indicating that AB-3A4 has potential as an antibody-drug conjugate (ADC). Here we describe preclinical results of AB-3A4 conjugated to the cytotoxic agent monomethyl auristatin E (AB-3A4-vcMMAE). Binding studies with KAAG1-positive cell lines, such as the SKOV-3 (ovarian), MDA-MB-231 (TNBC) and PC-3 (prostate) showed that AB-3A4-vcMMAE interacted with its antigen in a similar manner to the unconjugated AB-3A4. In cytotoxicity assays, AB-3A4-vcMMAE killed cancer cell lines expressing KAAG1 with an IC50 value of 1 - 2 nM, whereas it displayed no specific potency in KAAG1-low or -negative cells. SKOV-3 cells were subcutaneously implanted in SCID mice and allowed to grow to a volume of 150 - 200 mm3 after which four injections of AB-3A4-vcMMAE at 5 mg/kg were administered over two weeks. Rapid and sustained tumor regression was observed for several weeks post-injection. In PC-3 xenografts, a single injection of AB-3A4-vcMMAE at 3 mg/kg was sufficient to cause significant tumor regression and this efficacy was found to be dose-dependent between doses of 1 and 10 mg/kg. In parallel treatment groups, no significant tumor shrinkage was observed with either a control IgG-vcMMAE or a mixture of unconjugated AB-3A4 and free MMAE at a drug-antibody ratio corresponding to that of AB-3A4-vcMMAE. Furthermore, xenografts of TNBC MDA-MB-231 cells were significantly regressed following a single injection of AB-3A4-vcMMAE with no recurrence after several weeks post-treatment. Finally, using an intraperitoneal orthotopic model of ovarian cancer, treatment with AB-3A4-vcMMAE significantly increased the overall survival of mice compared to mice treated with the control ADC. Collectively, our results demonstrate the potent efficacy of AB-3A4-vcMMAE in several disease models and underscore the potential of this novel agent in ovarian cancer, TNBC and castration-resistant prostate cancer, three areas for which very few targeted therapies exist. Citation Format: Gilles B. Tremblay, Anna Moraitis, Dominique Bédard, Adriana Orimoto, Martine Pagé, Anne-Marie Mes-Masson, Mario Filion. AB-3A4: A novel KAAG1-targeting antibody-drug conjugate is active in models of ovarian carcinoma, triple-negative breast cancer and castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 666. doi:10.1158/1538-7445.AM2014-666

To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA. Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately. The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02). Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

Osteoarthritis (OA) is recognized to have a genetic component, and in this study, we aimed to replicate in a case-control study of men and women with clinical knee OA genetic associations in 12 candidate genes previously reported to be associated with OA. Twenty-five single-nucleotide polymorphisms were genotyped in 298 men and 305 women ages 50-86 who were diagnosed as having knee OA, as assessed both clinically and radiographically, and in 297 men and 299 women matched for age and ethnicity (controls). Standardized anteroposterior radiographs of the knee in extension were performed on each of the cases, and all cases met the American College of Rheumatology criteria for OA of the knee. Genotype and haplotype frequencies in cases and controls were compared separately in men and women. The 12 genes tested were AACT, ADAM12, BMP2, CD36, CILP, COX2, ESR1, NCOR2, OPG, TNA, TNFAIP6, and VDR. Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex. The strongest associations in terms of odds ratios (ORs) were a haplotype in ADAM12 (OR 7.1 [95% confidence interval (95% CI) 3.3-33.8]) and a haplotype in ESR1 (OR 3.6 [95% CI 1.18-10.98]) in women. The same ADAM12 haplotype (OR 2.54 [95% CI 1.2-5.4]) and a haplotype in the CILP gene (OR 0.38 [95% CI 0.23-0.62]) were the strongest associations in men. We found that genes previously identified by their association with subclinical features of knee OA or progression were also associated with clinical knee OA. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

Variants in the gene encoding the DLG5 scaffolding protein have been reported to be associated with increased risk of inflammatory bowel disease (IBD) and particularly Crohn's disease (Crohn disease; CD). These findings have not been uniformly replicated in follow-up studies. In this study we genotyped a cohort of 402 Canadian CD and 179 ulcerative colitis (UC) patients and 537 healthy controls for three IBD/CD-associated DLG5 variants. Our data reveal that the common DLG5 haplotype (A), which was previously considered protective for IBD, is associated with modest increases in risk for IBD (P=0.02) and CD (P=0.04). The effects of haplotype copy number on risk for IBD were minor, with the odds ratio (ORs) being 1.37 for the heterozygous risk genotype and 1.7 for the homozygous risk genotype. While we were unable to replicate the proposed association between the DLG5 c.113G>A variant and IBD, an association of IBD (P=0.02) and CD (P=0.04) with the rarer c.4136C>A variant was replicated in this cohort. These associations were restricted to the non-Jewish subjects in this cohort and were not detected in the Ashkenazi Jewish population studied here. Within the non-Jewish group, no associations were detected between the DLG5 variants and specific phenotypic features, such as site of disease, and there was no evidence of epistasis between DLG5 and any of the CD-associated CARD15 or SLC22A4/A5 gene variants. Together, the results indicate a role for DLG5 variants in IBD susceptibility and suggest that further studies are warranted to evaluate this role in different IBD populations and to determine the functional pathways that couple DLG5 variants to IBD.