Journal
CELLULAR IMMUNOLOGY
Volume 313, Issue -, Pages 59-66Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.cellimm.2017.01.003
Keywords
Immunogenicity; T cell epitopes; Pseudomonas exotoxin A; Domain II; Deimmunization; TAC; IL2 receptor; RIT
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Funding
- Intramural Research Program of the NIH National Cancer Institute, Center for Cancer Research [ZO1 BC008753]
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LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38 kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given. Published by Elsevier Inc.
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