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Background: ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody® with a masking peptide blocking the antigen binding site. ADG126 is designed to be preferentially activated in the tumor microenvironment (TME), with the goal of limiting on-target off-tumor toxicities and promoting prolonged exposure to active drug in the TME. Activated ADG126 binds to a unique and conserved epitope of CTLA-4 with species cross-reactivity. Nonclinical studies have demonstrated that activated ADG126 potentiates T cell activation and depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC) specifically in the TME. We present interim results from our ongoing Phase 1b/2 study (ADG126-1001, NCT04645069) on dose escalation and expansion of ADG126 monotherapy as well as dose escalation of ADG126 + toripalimab (Tori). Method: Pts with advanced solid tumors received ADG126 monotherapy (0.1, 0.3, 1, 3, 10, and 20 mg/kg) Q3W IV or ADG126 (6 or 10 mg/kg) + Tori (240mg) Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, anti-drug antibody (ADA), as well as ORR, DCR, DOR and PFS per RECIST 1.1. Result: As of Dec. 26, 2022, 30 pts have received ADG126 monotherapy. The median number of treatment cycles was 2 (range: 1-24). The median age was 63.5 (39-84) years. 43% of pts had ≥ 3 prior lines of therapies, and 47% had been previously treated with anti-PD-(L)1 and/or anti-CTLA-4 therapies. ADG126 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached. Only Grade (G) 1-2 TRAEs were reported; TRAEs ≥10% included diarrhea (17%), fatigue (17%), pruritus (13%), and rash (10%). Among 27 evaluable pts, DCR = 37%. One pt with ovarian serous carcinoma had a major CA125 response (90% reduction) and her disease was stable with ongoing treatment of ADG126 1 mg/kg at Cycle 24 (~16 months). In addition, 14 pts have received ADG126 + Tori in the dose escalation cohorts. The median age was 60 (36-85) years; 50% had ≥ 3 prior lines of therapies, and 43% received prior anti-PD-1 therapies. Both dose levels were well tolerated with no DLT. TRAEs (> 10%) included diarrhea (21%), fatigue (14%), pruritus (14%), rash (14%) and nausea (14%). After multiple cycles at 6 or 10 mg/kg Q3W, G3 TRAEs were observed in 21% (3/14) pts, including elevated liver function test/hepatitis, elevated lipase and diarrhea, which are immune-related, and sepsis. No G4/5 TRAEs have been reported. Among 12 evaluable pts, DCR = 58%, including 2 partial responses. Early efficacy signals were observed with continuous tumor shrinkage and stabilization in IO-resistant and cold tumors. Conclusion: The anti-CTLA-4 SAFEbody ADG126 shows favorable safety profiles in monotherapy up to 20 mg/kg and in combination with Tori up to 10 mg/kg. Furthermore, promising anti-tumor activity in heavily pre-treated patients was observed in the dose escalation phase. By enabling higher dose levels in combination with anti-PD-1 therapy, ADG126 may unleash the full therapeutic potential for proven and novel indications. Citation Format: Mihitha Ariyapperuma, John J. Park, Adnan Khattak, Gary Richardson, Anis Hamid, Michelle Morris, Anthony W. Tolcher, Boon Cher Goh, Justina Lam, Bartosz Chmielowski, Kristine She, Yanyan Zhang, Ai Li, Songmao Zheng, Guizhong Liu, Lvyu Zhu, Hongyan Wang, Xiaoxing Cui, Peter Luo, Jiping Zha. Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT227.

BackgroundDespite the proven diagnostic significance, the prognostic role of ANCA, in particular for assessing disease activity, remains questionable. Numerous studies have attempted to estimate the role of ANCA monitoring with different results and a lack of consensus on reported outcomes [1].ObjectivesTo analyze the relationship between ANCA level and clinical or laboratory parameters of disease activity.MethodsThis is a retrospective analysis of 38 patients with ANCA-associated vasculitis (granulomatosis with polyangiitis – 25 patients, microscopic polyangiitis – 6 patients and eosinophilic granulomatosis with polyangiitis – 7 patients) from a single center observed from 2015 till the end of 2020. The diagnosis of ANCA-associated vasculitis was performed according to the ACR 1990 criteria or the Chapel Hill Consensus Conference 2012 nomenclature. The study included 20 women (52.6%) and 18 men (47.4%). The average age of patients was 49 (27-62) years, the mean duration of the disease was 26 (6-120) months. The clinical data, initial Birmingham vasculitis activity score (BVAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ANCA (ELISA test) against proteinase-3 (PR-3) and myeloperoxidase (MPO) were evaluated. Spearman's correlation analysis was used to investigate the relationship between ANCA levels and ESR, CRP levels, BVAS activity index. The diagnostic value of ANCA in determining the active disease was evaluated by ROC analysis with an estimation of the area under the ROC curve (AUC). The definition of active disease included new, persistent, or worsening clinical signs and/or symptoms attributed to GPA, MPA, or EGPA and not related to prior damage [2].ResultsPositivity for MPO-ANCA was observed in 23.7% of patients, and for PR3-ANCA - in 76.3% of patients. The BVAS activity index averaged 16 (IQR-13) points. The mean CRP level was 47.9 (IQR-90.0) mg/L and the ESR level was 30.1 (IQR-33.5) mm/h. There was a positive correlation between the level of both ANCA and the BVAS index (r = 0.43; 95% CI 0.11-0.66; p 0.05), but a positive correlation was observed between CRP level and index BVAS activity (r = 0.41; 95% CI 0.05-0.67; p ConclusionThe level of ANCA in patients with ANCA-associated vasculitis correlates with the Birmingham vasculitis activity score, as well as with the level of ESR. Determination of ANCA level can be used not only to diagnose ANCA-associated vasculitis, but also to assess disease activity.References[1]Adam D. Morris, Anthony W. Rowbottom, Francis L. Martin, Alexander Woywodt and Ajay P. Dhaygude Kidney360 March 2021, 2 (3) 586-597; DOI: https://doi.org/10.34067/KID.0006432020[2]Chung, S. A., Langford, C. A., Maz, M., et al. (2021). 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis & rheumatology (Hoboken, N.J.), 73(8), 1366–1383. https://doi.org/10.1002/art.41773Disclosure of InterestsNone declared

s / Placenta 35 (2014) A1eA112 A7 tissues, ex vivo explants and trophoblast cell culture systems, ADAM12was immunolocalized to the distal ends of EVT columns and to highly-invasive matrix-degrading EVTs. Notably, a specific role for the secreted isoform, ADAM12S, in promoting trophoblast invasion, as well as EVT column outgrowth was demonstrated. ADAM12 gene expression and promoter activity were shown to be in part regulated by cyclic adenosine 30-50monophosphate (cAMP), and this effect was independent of PKA activity. We provide evidence that cAMP-directed induction of ADAM12 is controlled by the guanine nucleotide exchange factor Epac1, where inhibition of Epac1/Rap1a blocks EVT invasion. Our findings demonstrate the importance of ADAM12 in directing EVT column formation and trophoblast cell invasion, and highlight novel upstream factors controlling ADAM12 expression in the early placenta. SIFPAA. EX VIVO DUAL PERFUSION OF A HUMAN PLACENTAL COTELYDON e MODIFICATIONS OF ACCESS TO THE INTERVILLOUS SPACE Henning Schneider Department of Obstetrics and Gynecology, Inselspital eUniversity of Berne, Berne, Switzerland Ex vivo dual perfusion of a human placental cotelydon was first described by M. Panigel in Paris in 1967. After cannulation of a chorionic arterial and venous branch the corresponding segment of the fetal vasculature was perfused. A remnant of a spiral artery of the same cotyledon was catheterized. Imaging by cineradioangiography showed, that the flow picture of the fetal and maternal circuit for that one cotyledon came very close to the in vivo situation, which had been shown in Rhesus monkeys. In an attempt to simplify access to the IVS an adaptationwith penetration of the decidual plate with 3 to 5 cannulae was introduced. Energy dependant functions such as active transport of aminoacids from thematernal to the fetal circuit were still intact inspite of a delay of 20 to 30 min. needed to set up the preparation. This unexpected tolerance of prolonged ischemia may be explained by down regulation of metabolism as had been described for the transitional stage preceding torpor in hibernating animals. With medium with physically dissolved oxygen the supply of oxygen is only a fraction of the in vivo estimate of requirement. The special tolerance of chronic hypoxia of the perfused tissue can partially be explained by metabolic reprogramming with reduction in mitochondrial oxygen consumption and an increase in anaerobic glycolysis. Improving oxygen supply remains a major challenge for ex vivo dual perfusion. Different modes of increasing the oxygen carrying capacity of the medium such as equilibrationwith 95% of oxygen or use of erythrocytes or synthetic oxygen carriers have been unsatisfactory. Recent studies with direct measurement of oxygen content at different sites inside the IVS have shown that by increasing the number of maternal cannulae to 22 a considerable improvement in distribution of perfusate inside the IVS can be achieved. A systematic study to determine the optimal number of cannulae for the maternal perfusion circuit is in progress. THAN. IDENTIFICATION OF PLACENTAL FAILURE e THE KEY TO SAVING BABIES’ LIVES? Alexander Heazell a,b Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK; b St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK In high-income countries approximately 1 in 200 babies are stillborn. Stillbirth is associated with placental disease in up to 65% of cases. Detailed examination of the placenta offers the opportunity to describe processes leading to stillbirth, so that deaths might be prevented. Our research programme focuses on understanding placental abnormalities in stillbirth and applying this knowledge to identify pregnancies at greatest risk. Our systematic review verified that stillbirth is associated with a variety of placental abnormalities ranging from small placental size to specific histopathological entities. However, interpretation of these findings is hampered by variation in classification of “placental causes” of stillbirth and description of lesions. Our morphometric analyses demonstrated that stillbirths associated with fetal growth restriction (FGR) have a specific placental phenotype that is not associated with artefacts of storage or absent fetal circulation. This phenotype is more severe than in live born FGR infants and is evident in some stillbirths currently classified as “unexplained”. A similar analytical approach identified abnormalities of placental structure and dysfunction in groups at increased risk of stillbirth, including women reporting reduced fetal movements (RFM) or advanced maternal age. Thus, some placental causes of stillbirth display a recognisable phenotype, opening the possibility that this dysfunction could be detected antenatally. We therefore tested the hypothesis that adverse pregnancy outcome (APO) can be identified using markers of fetal wellbeing and placental function. In RFM, APO was associated with abnormal fetal heart rate, a small for gestational age fetus and low levels of progesterone, hCG and hPL; low hPL was associated with a 7-fold increase in APO. A pilot randomised controlled trial comparing standard management vs. intervention guided by ultrasound + hPL measurement found a statistically significant reduction in APO, with no increase in maternal anxiety. Thustargeted intervention in women with evidence of placental dysfunction may reduce stillbirths. NIH. HUMAN STEM CELLS FROM SINGLE BLASTOMERES REVEAL PATHWAYS OF EMBRYONIC OR TROPHOBLAST FATE SPECIFICATION Susan Fisher University of California, San Francisco, San Francisco, CA, USA There are major mechanistic differences among species in how initial cell fate decisions are made in embryos. To gain insights into lineage allocation in humans, we derived ten human embryonic stem cell lines from single blastomeres of four 8-cell embryos and one 12-cell embryo from a single couple (UCSFB1-10). Compared to a large panel of lines from blastocysts, they exhibited unique patterns of gene expression and DNA methylation that were highly indicative of trophoblastic competence. At a transcriptional level, UCSFB lines from different embryos were often more closely related than those from the same embryo. As predicted by the transcriptomic data, immunolocalization of eomesodermin and brachyury showed differential expression among blastomeres of 8-12-cell human embryos. The UCSFB lines formed derivatives of the three germ layers. Thus, out data suggested heterogeneity among early-stage blastomeres and that the UCSFB lines had unique properties, suggesting a more immature state than lines derived from blastocysts. Genes controlling extraembryonic or trophoblast development were hypomethylated in the UCSFB lines. Therefore, we investigated their trophoblast potential by forming embryonic bodies. Immunoanalyses of the outgrowths showed that the cultures contained cells with the morphology and antigenic profile of trophoblasts. Next, we asked whether we could derive human trophoblast stem cells from one of the lines. At day 3, trophoblast-like cells were manually dissected from the outgrowths and cultured using ourmethod for establishing lines of trophoblast progenitors from human placentas. The resulting cells could be passaged indefinitely. They immunostained, in a nuclear pattern, for transcription factors that are required for generation of the trophoblast lineage. Wewere also interested in their capacity in terms of forming the mature trophoblast cell types of the human placenta. In this regard, they form invasive cytotrophoblasts and multinucleated syncytiotrophoblasts. Thus, we succeeded in deriving human trophoblast stem cells. NI.1. EXPRESSION OF THE b-ISOFORM OF THE THROMBOXANE A2 RECEPTOR REGULATES MATERNAL AND FETAL DERIVED CHARACTERISTICS OF PRE-ECLAMPSIA Katie L. Powell , Veronica Stevens , Sharon McCracken , Vitomir Tasevski , Jonathan M. Morris , Anthony W. Ashton a Division of Perinatal Research, Kolling Institute of Medical Research, St Leonards NSW

Background: SAR566658 (SAR) is a maytansinoid-loaded ADC (huDS6-SPDB-DM4) targeting CA6, a specific glycol-epitope of MUC-1 over-expressed in solid tumors (pancreas 26%, ovary 55%, breast 30%, bladder 60%) and rarely in normal tissues. This FIH study was designed to assess the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and pharmacokinetic following SAR administration in Pts with CA6-expressing STs. Trial is funded by Sanofi. Methods: This Phase I study explored escalating intravenous doses of SAR administered as single agent every 3 weeks (q3w). An accelerated dose escalation scheme was used for the two first dose levels (DL), followed by a standard 3+3 dose escalation scheme. Results: 34 heavily pretreated Pts were enrolled including: 11M/23F, median age 58 years (range, 32-77), ECOG-PS ≤1, with a variety of advanced STs including ovary (13), pancreas (10) and breast (4). A total of 114 cycles (cy), median 2, (range,1-14) of SAR was administered across 9 DLs ranging from 10 to 240 mg/m2. DLTs were observed at the highest DL of 240 mg/m2 and included grade (Gr) 3 diarrhea at cy1 in 1 Pt and Gr3 keratitis at cy2 in 2 Pts. Anticipated toxicity was cornea, peripheral neuropathy, hematological and pulmonary. So far the number of Pts with these toxicities are: keratitis (all Gr: 11 Pts, including 2 Pts with Gr3), peripheral neuropathy (5 Pts, no Gr≥3), neutropenia (Gr3, 2 Pts), interstitial pneumonitis (1 Pt). Other than late occurrence of reversible corneal adverse events (AE) at 150 mg/m2, no dose-dependent AE was observed. Exposure to SAR (Cmax and AUC) increased with no major deviation from dose proportionality over doses of 20 to 240 mg/m2. Clearance was roughly constant over the doses with a low to moderate total variability. SAR 190 mg/m2 fulfills the criteria for RD: no DLT and manageable ocular AE versus highest DL. Clinical benefit was observed at doses ≥120 mg/m2: 1 partial response (breast), 1 PR to be confirmed (ovary), 3 stable disease (SD)>6months and 11 SDs were noted. A significant decrease in tumor marker was noted in 1 Pt. Conclusions: SAR has a favorable safety profile and encouraging antitumor activity. SAR at 190mg/m2 q3w was selected as the RD and is being confirmed in an ongoing extension cohort. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A73. Citation Format: Valentina Boni, Olivier Rixe, Drew Rasco, Carlos Gomez-Roca, Emiliano Calvo, John C. Morris, Anthony W. Tolcher, Sylvie Assadourian, Helene Guillemin, Jean-Pierre Delord. A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A73.