Journal
JOURNAL OF IMMUNOTHERAPY
Volume 31, Issue 9, Pages 871-884Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e318186c8b4
Keywords
tumor immunotherapy; bispecific antibody fragments; natural killer cells; Fc gamma receptor; CD19
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Funding
- Schickcdanz KinderKrebs Stiftung
- Staedtler Foundation
- Kind-Philipp-Stiftung fur Leukamieforschung
- DFG program [643]
- Wilhelm Sander Foundation
- University of Erlangen Children's Hospital
- Beitlich Foundation, Tuebingen
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A novel bispecific antibody-derived recombinant protein targeting leukemias and lymphomas was designed, a single-chain Fv triple body (sctb) consisting of 1 polypeptide chain with 3 scFvs connected in tandem. The distal scFvs were specific for the tumor antigen CD19, and the central scFv for the trigger molecule CD 16 (Fc gamma RIII) on natural killer (NK) cells and macrophages. We had previously built a disulphide stabilized (ds) bsscFv [19 x 16] with monovalent binding for CD19 from ds components. The sctb ds[19 x 16 x 19] also used ds components and displayed 3-fold greater avidity for CD19 than the bsscFv (K-D = 13 vs. 42 nM), whereas both had equal affinity for CD 16 (KD 58 nM). Plasma half-lives in mice were 4 and 2 hours for the setb and the bsscFv, respectively. In antibody-dependent cellular cytotoxicity reactions with human mononuclear cells as effectors, the setb promoted equal lysis of leukemic cell lines and primary cells from leukemia and lymphoma patients at 10-fold to 40-fold lower concentrations than the bsscFv. This new format may also be applicable to a variety of other tumor antigens and effector molecules. With half-maximum effective concentrations (EC50) in the low picomolar range, the sctb ds[19 x 16 x 19] is an attractive candidate for further preclinical evaluation.
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