949 First-in-human study of the first acid pH-sensitive and recycling CTLA-4 antibody that preserves the immune tolerance checkpoint to avoid immunotherapy-related adverse events in cancer patients

BackgroundCTLA-4 is the first immune checkpoint target for cancer immunotherapy. However, the clinical benefit of targeting CTLA-4 has been limited by suboptimal doses and early discontinuation due to immunotherapy-related adverse events (irAE). Our preclinical studies suggest that acid pH-sensitive anti-CTLA-4 antibodies that preserve CTLA-4 recycling and avoid lysosomal degradation are more effective for immunotherapy but largely devoid of immunotherapy-related adverse events (irAE) [1-6]. To test this new hypothesis in human, we initiated first-in-human study evaluating the safety and tolerability of ONC-392 in patients with advanced solid tumors.MethodsONC-392-001 Part A is a dose finding study of ONC 392, IV infusion, Q3W. Patients (pt) with advanced solid tumors who had progressed to standard of care cancer therapies with ≥1 measurable tumor were enrolled. Intra-patient dose-escalation were performed for 4 doses (0.1, 0.3, 1.0 and 3.0 mg/kg) and 6 pts for the final dose of 10.0 mg/kg. The primary endpoints are the safety and tolerability of ONC-392 for identifying recommended Phase II dose (RP2D).ResultsTen pts have received 2-11 cycles of ONC-392 treatment at dose levels ranging from 0.1 to 10 mg/kg. Pt characteristics: median age 62 (range 43-81), female/male: 7/3, White/Asian/Black: 6/3/1. Tumor types: 4 ovarian, 4 NSCLC, 1 cervical and 1 GE junction cancer. Prior line of treatment: 2-7. Six pts were in 10 mg/kg dose level and received 2-4 doses of the drug as of this writing. None of the 10 pts experienced dose limiting toxicity (DLT) or Gr 3-4 adverse events (AEs) in DLT period. The RP2D for ONC-392 monotherapy is 10 mg/kg. After the DLT period, 1 patient developed Gr 3-4 elevated amylase/lipase at 10 weeks after 4 cycle of 10 mg/kg. No other treatment-related severe AE was observed. Among eight evaluable pts, 7/8 (87.5%) had stable disease (SD) after three cycle of treatment, and beneficial clinical efficacy activities was observed in 3/8 (37.5%) pts. Among them, a stage 4B ovarian cancer patient had stayed in treatment for 30 weeks till disease progression, and 2/2 evaluable PD(L)-1 antibody-refractory NSCLC patients were either eligible for surgery or had significant tumor shrinkage.ConclusionsONC-392 monotherapy is well tolerated with very low irAE rate. The RP2D for ONC-392 monotherapy is 10 mg/kg. The acid pH-sensitive anti-CTLA-4 mAb that preserves CTLA-4 recycling and avoids lysosomal degradation was safe and well tolerated. Our work paves the way for significant increase of drug exposure to reach full immunotherapeutic potential of CTLA-4 targeting.AcknowledgementsThe study is sponsored by OncoC4, Inc with the support of NCI SBIR grant R44CA250824.Trial RegistrationNCT04140526ReferencesDu X, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018;28(4):433–447.Du X, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28(4):416–432.Liu Y, Zheng P. How does an anti-CTLA-4 antibody promote cancer immunity? Trends Immunol 2018;39(12):953–956.Zhang Y, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Research 2019;29(8):609–627.Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 2020;41(1):4–12.Zhang P, et al. Mechanism- and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies. Cancers (Basel), 2020;12(2):284.Ethics ApprovalThis study obtained ethic approval from WIRB with Study #20193108. All participants gave informed consent before taking part of the study.ConsentN/A.

Cyclodextrin Complexation as a Way of Increasing the Aqueous Solublity and Staility of Carvedilol

We studied the effect of several CDs on carvedilol’s solubility and chemical stability in various aqueous media. Our present results show that it is possible to achieve a carvedilol concentration of 5 mg/mL (12.3 mM) in the presence of 5 eq of γCD or RAMEB in an aqueous medium with an acceptable acid pH (between 3.5 and 4.7). Carvedilol formed 1:1 inclusion complexes but those with RAMEB appear to be stronger (K = 317 M−1 at 298 K) than that with γCD (K = 225 M−1 at 298 K). The complexation of carvedilol by RAMEB significantly increased the drug’s photochemical stability in aqueous solution. These results might constitute a first step towards the development of a novel oral formulation of carvedilol.

Influence of artificial aging: mechanical and physicochemical properties of dental composites under static and dynamic compression

Objective The aim of the study was to evaluate the influence of filler content, degradation media and time on the mechanical properties of different dental composites after in vitro aging. Materials and Methods Specimens (1 mm3) of three commercially available composites (GrandioSO®, Arabesk Top®, Arabesk Flow®) with respect to their filler content were stored in artificial aging media: artificial saliva, ethanol (60%), lactic acid (pH 5) and citric acid (pH 5). Parameters (Vickers microhardness, compressive strength, elastic modulus, water sorption and solubility) were determined in their initial state (control group, n = 3 for microhardness, n = 5 for the other parameters) and after 14, 30, 90 and 180 days (n = 3 for microhardness, n = 5 for the other parameters for each composite group, time point and media). Specimens were also characterized with dynamic-mechanical-thermal analysis (compression tests, F = ± 7 N; f = 0.5 Hz, 1 Hz and 3.3 Hz; t = 0–170 °C). Results Incorporation of fillers with more than 80 w% leads to significantly better mechanical properties under static and dynamic compression tests and a better water sorption behavior, even after chemical degradation. The influence of degradation media and time is of subordinate importance for chemical degradation. Conclusion Although the investigated composites have a similar matrix, they showed different degradation behavior. Since dentine and enamel occur only in small layer thickness, a test specimen geometry with very small dimensions is recommended for direct comparison. Moreover, the use of compression tests to determine the mechanical parameters for the development of structure-compatible and functionally adapted composites makes sense as an additional standard. Clinical relevance Preferential use of highly filled composites for occlusal fillings is recommended.

Galactomannans for Entrapment of Gliomastix murorum Laccase and Their Use in Reactive Blue 2 Decolorization

In the present study, a novel laccase from ascomycete Gliomastix murorum was produced in agro-industrial wastes and entrapped in galactomannan beads for Reactive Blue 2 (Rb-2) decolorization. The maximum laccase production in agave bagasse-based medium occurred at 72 h (1798.6 UL−1). Entrapped laccase decolorized ˃80% of 0.5 mM Rb-2 in 2 h without the addition of redox mediator. Km for Rb-2 substrate was 1.42 mM, with a Vmax of 1.19 µmol min−1 for entrapped laccase. Galactomannan matrices produce stability to acid pH (2–5) and temperatures from 20–70 °C. Reusability assays showed that entrapped laccase could retain efficient Rb-2 decolorization of ˃80% six times. In general, galactomannan used for entrapment of laccase provides economic advantages in large-scale wastewater treatment due to its natural origin and efficient results.

Characterization and Land Suitability Evaluation for Cocoyam in Southern Nigeria

The soils on diverse landforms in Ikot Esidem, Southern Nigeria were characterized and their suitability evaluated for three varieties of cocoyam. The study area was stratified into flood plains, inland valleys, gentle slopes and crest. The results indicate that sand (30-78%) dominated pedons of gentle slopes and crest while silt (25-55%) and clay (19-51%) dominated the pedons of flood plains and inland valleys. The soils of flood plains and inland valleys were moderately acid (pH 5.0-5.7), medium to high in organic carbon (6.3-20.5 g/kg) and medium to high in base saturation (BS) (46-90%). The gentle slopes and crest units were strongly acid (pH 4.0-5.1), low in organic carbon (4.0-11.3 g/kg) and base saturation (20.5-34.7%). The land suitability evaluated the flood plains and inland valleys as moderately suitable and the gentle slopes and crest as not suitable for Dasheen Type Taro. The flood plains and inland valleys were also evaluated moderately suitable, whereas gentle slopes and crest were marginally suitable for Eddoe Type Taro. Efficient water control drainage and erosion control will enhance cocoyam cultivation depending on terrain type.

Salmonella enterica serovar Typhi genomic regions involved in low pH resistance and in invasion and replication in human macrophages

Purpose Salmonella enterica serovar Typhi, the etiological agent of typhoid fever, causes a systemic life-threatening disease. To carry out a successful infection process, this bacterium needs to survive alkaline and acid pH conditions presented in the mouth, stomach, small intestine, and gallbladder. Therefore, in this work, a genetic screening to identify S. Typhi genes involved in acid and circumneutral pH resistance was performed. Methods A collection of S. Typhi mutants deleted of fragments ranging from 6 to 80 kb were obtained by the Datsenko and Wanner method. Bacterial growth rate assays of each mutant were performed to identify S. Typhi genes involved in circumneutral and acid pH resistance. S. Typhi mutants deficient to growth at specific pH were evaluated in their capacity to invade and replicate in phagocytic cells. Results In this work, it is reported that S. Typhi ∆F4 (pH 4.5), S. Typhi ∆F44 (pH 4.5, 5.5, and 6.5), and S. Typhi ∆F73 (pH 4.5, 5.5, 6.5, and 7.5) were deficient to grow in the pH indicated. These three mutant strains were also affected in their ability to invade and replicate in human macrophages. Conclusions S. Typhi contains defined genomic regions that influence the survival at specific pH values, as well as the invasion and replication inside human cells. Thus, this genetic information probably allows the bacteria to survive in different human compartments for an efficient infection cycle.