Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug
Byung Chull An,1 Yeo-Sang Yoon,1 Ho Jin Park,1 Sangkyun Park,1 Tai Yeub Kim,1 Jun Young Ahn,1 Daebeom Kwon,1 Oksik Choi,1 Jin Young Heo,1 Yongku Ryu,1 Joong-Hyun Kim,2 Heejong Eom,2 Myung Jun Chung1 1R&D Center, Cell Biotech, Co., Ltd., Gimpo-si, Gyeonggi-do, Korea; 2Laboratory Animal Center, Os...
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Dove Medical Press
2021
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oai:doaj.org-article:8a159f8c60c74bf8961932b1f55b50ba2021-11-28T19:13:10ZToxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug1177-8881https://doaj.org/article/8a159f8c60c74bf8961932b1f55b50ba2021-11-01T00:00:00Zhttps://www.dovepress.com/toxicological-evaluation-of-a-probiotic-based-delivery-system-for-p8-p-peer-reviewed-fulltext-article-DDDThttps://doaj.org/toc/1177-8881Byung Chull An,1 Yeo-Sang Yoon,1 Ho Jin Park,1 Sangkyun Park,1 Tai Yeub Kim,1 Jun Young Ahn,1 Daebeom Kwon,1 Oksik Choi,1 Jin Young Heo,1 Yongku Ryu,1 Joong-Hyun Kim,2 Heejong Eom,2 Myung Jun Chung1 1R&D Center, Cell Biotech, Co., Ltd., Gimpo-si, Gyeonggi-do, Korea; 2Laboratory Animal Center, Osong Medical Innovation Foundation, Chungbuk, Cheongju, 28160, KoreaCorrespondence: Myung Jun Chung Tel +82-31-987-6205Fax +82-31-987-6216Email ceo@cellbiotech.comPurpose: This study aimed to toxicological evaluate a probiotics-based delivery system for p8 protein as an anti-colorectal cancer drug.Introduction: Lactic acid bacteria (LAB) have been widely ingested for many years and are regarded as very safe. Recently, a Pediococcus pentosaceus SL4 (PP) strain that secretes the probiotic-derived anti-cancer protein P8 (PP-P8) has been developed as an anti-colorectal cancer (CRC) biologic by Cell Biotech. We initially identified a Lactobacillus rhamnosus (LR)-derived anti-cancer protein, P8, that suppresses CRC growth. We also showed that P8 penetrates specifically into CRC cells (DLD-1 cells) through endocytosis. We then confirmed the efficacy of PP-P8, showing that oral administration of this agent significantly decreased tumor mass (∼ 42%) relative to controls in a mouse CRC xenograft model. In terms of molecular mechanism, PP-P8 induces cell-cycle arrest in G2 phase through down-regulation of Cyclin B1 and Cdk1. In this study, we performed in vivo toxicology profiling to obtain evidence that PP-P8 is safe, with the goal of receiving approval for an investigational new drug application (IND).Methods: Based on gene therapy guidelines of the Ministry of Food and Drug Safety (MFDS) of Korea, the potential undesirable effects of PP-P8 had to be investigated in intact small rodent or marmoset models prior to first-in-human (FIH) administration. The estimated doses of PP-P8 for FIH are 1.0× 1010 – 1.0× 1011 CFU/person (60 kg). Therefore, to perform toxicological investigations in non-clinical animal models, we orally administered PP-P8 at doses of 3.375 × 1011, 6.75 × 1011, and 13.5× 1011 CFU/kg/day; thus the maximum dose was 800– 8000-fold higher than the estimated dose for FIH.Results: In our animal models, we observed no adverse effects of PP-P8 on clinicopathologic findings, relative organ weight, or tissue pathology. In addition, we observed no inflammation or ulceration during pathological necropsy.Conclusion: These non-clinical toxicology studies could be used to furnish valuable data for the safety certification of PP-P8.Keywords: biologics, therapeutic protein, probiotics derived anti-cancer protein P8, Pediococcus pentosaceus SL4, Lactobacillus rhamnosus, colorectal cancer, drug delivery system, protein secretion system, oral administration, non-clinical trial, toxicology findingAn BCYoon YSPark HJPark SKim TYAhn JYKwon DChoi OHeo JYRyu YKim JHEom HChung MJDove Medical Pressarticlebiologicstherapeutic proteinprobiotics derived anti-cancer protein p8pediococcus pentosaceus sl4lactobacillus rhamnosuscolorectal cancerdrug delivery systemprotein secretion systemoral administrationnon-clinical trialtoxicology findingTherapeutics. PharmacologyRM1-950ENDrug Design, Development and Therapy, Vol Volume 15, Pp 4761-4793 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
biologics therapeutic protein probiotics derived anti-cancer protein p8 pediococcus pentosaceus sl4 lactobacillus rhamnosus colorectal cancer drug delivery system protein secretion system oral administration non-clinical trial toxicology finding Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
biologics therapeutic protein probiotics derived anti-cancer protein p8 pediococcus pentosaceus sl4 lactobacillus rhamnosus colorectal cancer drug delivery system protein secretion system oral administration non-clinical trial toxicology finding Therapeutics. Pharmacology RM1-950 An BC Yoon YS Park HJ Park S Kim TY Ahn JY Kwon D Choi O Heo JY Ryu Y Kim JH Eom H Chung MJ Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| description |
Byung Chull An,1 Yeo-Sang Yoon,1 Ho Jin Park,1 Sangkyun Park,1 Tai Yeub Kim,1 Jun Young Ahn,1 Daebeom Kwon,1 Oksik Choi,1 Jin Young Heo,1 Yongku Ryu,1 Joong-Hyun Kim,2 Heejong Eom,2 Myung Jun Chung1 1R&D Center, Cell Biotech, Co., Ltd., Gimpo-si, Gyeonggi-do, Korea; 2Laboratory Animal Center, Osong Medical Innovation Foundation, Chungbuk, Cheongju, 28160, KoreaCorrespondence: Myung Jun Chung Tel +82-31-987-6205Fax +82-31-987-6216Email ceo@cellbiotech.comPurpose: This study aimed to toxicological evaluate a probiotics-based delivery system for p8 protein as an anti-colorectal cancer drug.Introduction: Lactic acid bacteria (LAB) have been widely ingested for many years and are regarded as very safe. Recently, a Pediococcus pentosaceus SL4 (PP) strain that secretes the probiotic-derived anti-cancer protein P8 (PP-P8) has been developed as an anti-colorectal cancer (CRC) biologic by Cell Biotech. We initially identified a Lactobacillus rhamnosus (LR)-derived anti-cancer protein, P8, that suppresses CRC growth. We also showed that P8 penetrates specifically into CRC cells (DLD-1 cells) through endocytosis. We then confirmed the efficacy of PP-P8, showing that oral administration of this agent significantly decreased tumor mass (∼ 42%) relative to controls in a mouse CRC xenograft model. In terms of molecular mechanism, PP-P8 induces cell-cycle arrest in G2 phase through down-regulation of Cyclin B1 and Cdk1. In this study, we performed in vivo toxicology profiling to obtain evidence that PP-P8 is safe, with the goal of receiving approval for an investigational new drug application (IND).Methods: Based on gene therapy guidelines of the Ministry of Food and Drug Safety (MFDS) of Korea, the potential undesirable effects of PP-P8 had to be investigated in intact small rodent or marmoset models prior to first-in-human (FIH) administration. The estimated doses of PP-P8 for FIH are 1.0× 1010 – 1.0× 1011 CFU/person (60 kg). Therefore, to perform toxicological investigations in non-clinical animal models, we orally administered PP-P8 at doses of 3.375 × 1011, 6.75 × 1011, and 13.5× 1011 CFU/kg/day; thus the maximum dose was 800– 8000-fold higher than the estimated dose for FIH.Results: In our animal models, we observed no adverse effects of PP-P8 on clinicopathologic findings, relative organ weight, or tissue pathology. In addition, we observed no inflammation or ulceration during pathological necropsy.Conclusion: These non-clinical toxicology studies could be used to furnish valuable data for the safety certification of PP-P8.Keywords: biologics, therapeutic protein, probiotics derived anti-cancer protein P8, Pediococcus pentosaceus SL4, Lactobacillus rhamnosus, colorectal cancer, drug delivery system, protein secretion system, oral administration, non-clinical trial, toxicology finding |
| format |
article |
| author |
An BC Yoon YS Park HJ Park S Kim TY Ahn JY Kwon D Choi O Heo JY Ryu Y Kim JH Eom H Chung MJ |
| author_facet |
An BC Yoon YS Park HJ Park S Kim TY Ahn JY Kwon D Choi O Heo JY Ryu Y Kim JH Eom H Chung MJ |
| author_sort |
An BC |
| title |
Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| title_short |
Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| title_full |
Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| title_fullStr |
Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| title_full_unstemmed |
Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug |
| title_sort |
toxicological evaluation of a probiotic-based delivery system for p8 protein as an anti-colorectal cancer drug |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/8a159f8c60c74bf8961932b1f55b50ba |
| work_keys_str_mv |
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