Abstract
Randomized studies with gemtuzumab ozogamicin have validated CD33 as a target for antigen-specific immunotherapy of acute myelogenous leukemia (AML). Here, we investigated the potential of CD33/CD3-directed tandem diabodies (TandAbs) as novel treatment approach for AML. These tetravalent bispecific antibodies provide two binding sites for each antigen to maintain the avidity of a bivalent antibody and have a molecular weight exceeding the renal clearance threshold, thus offering a longer half-life compared to smaller antibody constructs. We constructed a series of TandAbs composed of anti-CD33 and anti-CD3 variable domains of diverse binding affinities and profiled their functional properties in CD33+ human leukemia cell lines, xenograft models, and AML patient samples. Our studies demonstrated that several CD33/CD3 TandAbs could induce potent, dose-dependent cytolysis of CD33+ AML cell lines. This effect was modulated by the effector-to-target cell ratio and strictly required the presence of T cells. Activation and proliferation of T cells and maximal AML cell cytolysis correlated with high avidity to both CD33 and CD3. High-avidity TandAbs were broadly active in primary specimens from patients with newly diagnosed or relapsed/refractory AML in vitro, with cytotoxic properties independent of CD33 receptor density and cytogenetic risk. Tumor growth delay and inhibition were observed in both prophylactic and established HL-60 xenograft models in immunodeficient mice. Our data show high efficacy of CD33/CD3 TandAbs in various preclinical models of human AML. Together, these findings support further study of CD33/CD3 TandAbs as novel immunotherapeutics for patients with AML. Clin Cancer Res; 22(23); 5829-38. ©2016 AACR.
Highlights
Transient receptor potential vanilloid (TRPV1) is a multi-subunit cation-permeating channel assembled from four identical subunits jointly surrounding the ion-conducting pore (Caterina et al, 1997; Clapham D.E. 2003; Liao et al, 2013)
We found biased mixing in higher ratios of S512F mutants to wild type produced more than
The results suggested that channel activations of TRPV1 were far from the attainable maxima when only one capsaicin-binding site was occupied by vanilloids
Summary
Transient receptor potential vanilloid (TRPV1) is a multi-subunit cation-permeating channel assembled from four identical subunits jointly surrounding the ion-conducting pore (Caterina et al, 1997; Clapham D.E. 2003; Liao et al, 2013). Built for detecting imminent tissue injury, TRPV1 must be sensitive enough to detect the insult and deliver a timely response. It obliges just sufficient sensitivity for sensible decoding of external or internal inflicts about to compromise the animal's physiological capacity. TRPV1 provides a substrate for creating a complex of the potential to broadly quantify combinations of environmental biochemical events. Micro-fluorometry was employed frequently to quantify intracellular Ca2+ rise from ionic influx through rTRPV1
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