Antikor (United Kingdom)

Abstract Antibody Drug Conjugates (ADCs) have failed to deliver the successes seen in breast and urological tumours in Gastro-intestinal tumours such as stomach, colorectal and pancreatic due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. Approaches utilizing full-length Immunoglobulins dominate the industry, however, antibody fragments (e.g. single-chain Fvs-scFvs), which have many advantages including rapid tumour penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favourable biophysical properties, leading to a new product class tailored for solid tumours. Antikor has two FDC products in development for solid tumours, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045, to be disclosed). ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumour ablation effects in breast, ovarian and gastric cancer xenograft models and superior tolerability compared to an ADC in rat toxicology studies at a dose of 1mg/kg/weekly. Quantitative payload tumour uptake and fluorescent immuno-histological studies demonstrate superior solid tumour penetration across the entire tumour and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology PLC, Antikor is taking ANT-043 into development. ANT-045, which emerged from Antikor’s proprietary FDC ‘discovery engine’, is progressing towards IND-filing and updated data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. ANT-045 has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and superior in vivo tumour cure efficacy, compared to a leading clinical stage benchmark ADC. This presentation will focus on Antikor’s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate first-in-class products for difficult to treat solid tumours for patient benefit and promising to succeed where ADCs have failed to make an impact. Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Soraya Diez-Posada, Bryan Edwards, Anja Pomowski, Isabel Perez-Castro, Sam Ness, Laura Bouche, Jeaniffer Yap, Howard Desmond, Lowri Davies, Malcolm Ngiam, Quinn Xue. Gastric cancerantibody fragment drug-conjugates (FDCs): Applying a successful concept to solid tumours [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 1530.

e17601 Background: Notch signalling is implicated in tumorigenesis prompting scientists to research and develop anti-Notch therapeutics. Drugging the Notch pathway has been a challenge due to severe G-I toxicity seen by many small-molecule inhibitors. Mastermind is a key nuclear factor that mediates Notch activity. We generated a novel protein drug, Syntana-4, that inhibits the Notch pathway at the Mastermind transcriptional level. Syntana-4 consists of the cell penetrating domain of Antennapedia, fused to a truncated peptide from Mastermind-like (MAML) that behaves in a dominant-negative fashion inhibiting Notch. Syntana-4 translocates into the cell nucleus, suppressing Notch activity and inducing apoptosis in Notch-driven cancer cells. Methods: We have conducted pharmacokinetics (PK), pharmacodynamics (PD) and toxicology studies, in combination with innovative imaging including in vivo flow cytometry and whole-body fluorescence reflectance imaging to define the behaviour of Syntana-4, determine its mode of action and establish a safety and efficacy profile in an orthotopic model of breast cancer in SCID mice based on the implantation of MDA-MB-231 cells into mammary fat pads. Samples of blood and tissues were examined for toxicity, apoptosis and immunogenicity. Results: We found that Syntana-4 was well-tolerated by normal cells and organs and was not immunogenic. Also, it was shown that free, non-internalized drug was rapidly cleared from the circulation. Whole body imaging showed that the drug in tissues was cleared within 24 hrs. Assessment of tumor growth demonstrated a reduction in tumor growth as evidenced by an overall increase of less than 50% in the intensity of fluorescence signal in the treated group compared to a 3-fold increase in signal and thus tumour size in untreated group by day 14. Conclusions: Syntana-4, a Mastermind inhibitor, was found to be well-tolerated and non-immunogenic in healthy animals. This drug targets the oncogenic Notch mechanism and can be applied across tumours with genetic defects in Notch signalling including breast, prostate, etc. We have demonstrated the utility of an innovative molecular imaging system emulating a clinical ‘phase I/II’ study in an orthotopic cancer model in order to measure the biodistribution, PK, PD, mode of action, toxicity and efficacy of a first-in-class biological therapy prior to entering the clinic. This innovative approach could be useful for accurate selection of lead drug candidates prior to entering clinical development.

BackgroundConsent rates for postmortem (PM) examination in the perinatal and paediatric setting have dropped significantly in the United Kingdom, the United States, and the Western Europe. We explored the factors that act as facilitators or barriers to consent and identified processes and practices that support parental decision‐making.MethodsA qualitative study conducted with bereaved parents, parent advocates, and health care professionals in the United Kingdom. Analysis was conducted on 439 free‐tect comments within a cross‐sectional survey, interviews with a subset of 20 survey respondents and 25 health professionals, and a focus group with five parent advocates.ResultsThree broad parental decision‐making groups were identified: 1, “Not open to postmortem examination”; 2, “Consent regardless of concerns”; and 3, “Initially undecided.” Decisional drivers that were particularly important for this “undecided” group were “the initial approach,” “adjustment and deliberation,” “detailed discussion about the procedure,” and “formal consent.” The way in which these were managed by health care staff significantly impacted whether those parents' consented to PM, particularly for those who are ambivalent about the procedure.ConclusionsWe propose a set of recommendations to improve the way PM counselling and consent is managed. Adopting such measures is likely to lead to improved family experience and more consistent and high‐quality discussion regarding PM.

Upaya yang dilakukan oleh pemerintah untuk menumbuhkan nilai-nilai pendidikan antikorupsi disekolah, salah satunya memasukkan kedalam kurikulum sekolah dengan cara mengintegrasikan kedalam mata pelajaran, bertujuan untuk menanamkan nilai dan sikap hidup anti korupsi kepada warga sekolah. Jenis penelitian ini adalah kualitatif. Dalam pengumpulan data metode yang digunakan adalah wawancara, observasi, dan dokumentasi yang didukung dengan data teoritis melalui telaah pustaka (library research).
 Penelitian menunjukkan bahwa, Pendidikan Antikorupsi terintegrasi studi pada mata pelajaran Akidah akhlak dan Pendidikan Kewarganegaraan sudah diterapkan di Madrasah Tsanawiyah Al-Yusra Gorontalo. Penerapan nilai-nilai pendidikan antikorupsi, terintegrasi studi pada mata pelajaran Akidah akhlak dan Pendidikan Kewarganegaraan, diterapkan melalui perencanaan, pelaksanaan dan evaluasi, dilakukan dengan penanaman nilai antikorupsi, meliputi: jujur, disiplin, kerja sama, sederhana, peduli, mandiri, ketulusan, integritas, kewarganegaraan, yang relevan dengan materi bahasan, yang dapat diamati dari sikap siswa melalui Lingkungan sosial peserta didik, dan nilai-nilai islami peserta didik.

A technique for determining the adhesion of a liquid-glass masonry mortar to acid-proof ceramics in anticorrosion linings is described. The results of studying adhesion in the linings under the action of certain types of chemically aggressive environments are given.