First-in-class monoclonal antibody (mAb) PBP1510 targeting pancreatic adenocarcinoma upregulated factor (PAUF) for pancreatic cancer (PC) treatment: Preclinical perspectives
| العنوان: | First-in-class monoclonal antibody (mAb) PBP1510 targeting pancreatic adenocarcinoma upregulated factor (PAUF) for pancreatic cancer (PC) treatment: Preclinical perspectives |
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| المؤلفون: | Kedar Diwakar Mandakhalikar, Sang Seok Koh, Seong-Yun Jeong, Deborah Moshinsky, Peggy Feyaerts, Ratna Karuna, Jamie Kim, Litha Jaison, Sumita Pradhan, Yeon Jeong Kim, Jin Park |
| المصدر: | Journal of Clinical Oncology. 40:e16274-e16274 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Oncology |
| الوصف: | e16274 Background: PAUF has been shown to induce PC cell proliferation, angiogenesis and evasion of immune surveillance, thereby promoting tumour progression and metastasis. PBP1510, a novel humanized IgG1 mAb developed by Prestige Biopharma Limited, Singapore, binds to and neutralizes PAUF with high specificity and affinity. With no available targeted therapies against PAUF, the first in its class, PBP1510, has been granted Orphan Drug Designation by EMA, US FDA and Korea MFDS. Methods: To assess inhibition of migration and invasion of PC in vitro, PC cell lines (CFPAC-1 and BxPC-3) with high expression levels of PAUF, and primary PC cells extracted from patients were treated with PBP1510 or human IgG (negative control). Suitability of cynomolgus monkey as animal model for pharmacokinetic (PK) and toxicity studies was verified by comparing binding affinities of PBP1510 to human and monkey PAUF. PK characteristics and immunogenicity of PBP1510 (up to 20 mg/kg), were examined in single dose studies in 6 monkeys. A 4-week repeated dose toxicity study was also conducted in 32 monkeys with PBP1510 (up to 40 mg/kg). An in vitro tissue cross-reactivity study was also conducted in a full panel of normal human tissues, to assess potential toxicity in humans. Results: PBP1510 suppressed the proliferation of the PC cell lines compared to negative control. The migration and invasion of PBP1510 treated PC cell lines as well as the primary tumour cells from patients was significantly reduced compared to the respective control groups in vitro. Similarity in binding affinity of PBP1510 to human PAUF and monkey PAUF, and amino acid sequence homology between human and monkey PAUF, suggest that monkey is an appropriate animal species for toxicity and PK studies of PBP1510. In monkey studies, a dose-proportional increase in systemic exposure was observed at low and high doses. PBP1510 at doses up to 40 mg/kg was well tolerated by study animals and no notable local or systemic toxicity was observed. Low immunogenic profile of PBP1510 was indicated by an absence of anti-PBP1510 antibodies till up to 57 days (8 doses and 28-day recovery period). These data are used to simulate human PK profile and to derive the starting dose and maximum escalated dose for the upcoming Phase 1 clinical studies. Cross-reactivity results did not reveal non-specific binding of PBP1510 in the human tissues except in the cytoplasm of acinar and duct epithelium in the salivary gland which is not expected to be of major toxicologic significance. Conclusions: The efficacy and safety data presented here, along with the data from in vivo mouse studies demonstrating superior anti-tumour activity of PBP1510 treatment, support further clinical development of PBP1510 as a novel anti-cancer agent to treat PAUF-positive PC. The pivotal step of advancing PBP1510 into initial human studies is now in progress. |
| تدمد: | 1527-7755 0732-183X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::8ef6f135f39dd0d985d96fa6d31eb9d2 https://doi.org/10.1200/jco.2022.40.16_suppl.e16274 |
| رقم الأكسشن: | edsair.doi...........8ef6f135f39dd0d985d96fa6d31eb9d2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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