PMID- 34141870
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210619
IS  - 2372-7705 (Print)
IS  - 2372-7705 (Electronic)
IS  - 2372-7705 (Linking)
VI  - 21
DP  - 2021 Jun 25
TI  - Preclinical evaluation of a novel antibody-drug conjugate targeting DR5 for 
      lymphoblastic leukemia therapy.
PG  - 329-339
LID - 10.1016/j.omto.2021.04.013 [doi]
AB  - Acute lymphoblastic leukemia (ALL) is an aggressive hematological neoplasm 
      resulting from immature lymphoid precursors. An antibody-drug conjugate (ADC), 
      coupling a small molecule covalently with a targeting antibody, can specifically 
      kill tumor cells. Death receptor 5 (DR5) is considered as a promising anti-tumor 
      drug target. In this study, we describe the preclinical evaluation of a novel 
      DR5-targeting ADC (Oba01) as a potential therapeutic against ALL. Oba01 utilizes 
      anti-DR5 humanized monoclonal antibody (zaptuzumab) coupled via a cleavable 
      linker to monomethyl auristatin E (MMAE). Oba01 can specifically bind to DR5 on 
      the tumor cells and transfer into lysosome via DR5-mediated endocytosis. It then 
      effectively releases the MMAE, which can bind to the tubulin and prevent its 
      aggregation, thereby leading to a significant inhibition of proliferation and 
      cell death in tumor cells. Additionally, Oba01 displays significant 
      dose-dependent tumoricidal activity in cell-derived xenograft (CDX) and 
      patient-derived xenograft (PDX) mouse models. More importantly, toxicity analysis 
      of Oba01 showed a favorable safety profile, and pharmacokinetic analysis 
      illustrated an excellent stability and tolerability in rats and cynomolgus 
      monkeys. Taken together, our data conclusively demonstrate that Oba01 is an 
      attractive candidate for further clinical trials in DR5-positive ALL patients.
CI  - (c) 2021 The Author(s).
FAU - Zhang, Shuyong
AU  - Zhang S
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
AD  - Obio Technology (Shanghai) Corp, Ltd., No. 908, Building 19, Ziping Road, Pudong 
      New District, Shanghai 201321, China.
FAU - Zhou, Dongdong
AU  - Zhou D
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
FAU - Zheng, Chao
AU  - Zheng C
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
FAU - Xiong, Peng
AU  - Xiong P
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
FAU - Zhu, Wan
AU  - Zhu W
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
FAU - Zheng, Dexian
AU  - Zheng D
AD  - Yantai Obioadc Biomedical Technology Ltd., Yantai, China.
AD  - Obio Technology (Shanghai) Corp, Ltd., No. 908, Building 19, Ziping Road, Pudong 
      New District, Shanghai 201321, China.
LA  - eng
PT  - Journal Article
DEP - 20210429
PL  - United States
TA  - Mol Ther Oncolytics
JT  - Molecular therapy oncolytics
JID - 101666776
PMC - PMC8173093
OTO - NOTNLM
OT  - ADC
OT  - ALL
OT  - DR5
OT  - Oba01
OT  - acute lymphoblastic leukemia
OT  - antibody-drug conjugate
OT  - death receptor 5
OT  - preclinical evaluation
OT  - targeted therapy
COIS- The authors declare no competing interests.
EDAT- 2021/06/19 06:00
MHDA- 2021/06/19 06:01
PMCR- 2021/04/29
CRDT- 2021/06/18 06:50
PHST- 2020/11/18 00:00 [received]
PHST- 2021/04/25 00:00 [accepted]
PHST- 2021/06/18 06:50 [entrez]
PHST- 2021/06/19 06:00 [pubmed]
PHST- 2021/06/19 06:01 [medline]
PHST- 2021/04/29 00:00 [pmc-release]
AID - S2372-7705(21)00063-2 [pii]
AID - 10.1016/j.omto.2021.04.013 [doi]
PST - epublish
SO  - Mol Ther Oncolytics. 2021 Apr 29;21:329-339. doi: 10.1016/j.omto.2021.04.013. 
      eCollection 2021 Jun 25.