Visible Light-Gating Responsive Nanochannel for Controlled Release of the Fungicide.

Fungicides have been widely used to protect crops from the disease of pythium aphanidermatum (PA). However, excessive use of synthetic fungicides can lead to fungal pathogens developing microbicide resistance. Recently, biomimetic nano-delivery systems have been used for controlled release, reducing the overuse of fungicides, and thereby protecting the environment. In this paper, inspired by chloroplast membranes, visible light biomimetic channels are constructed by using retinal, the main component of green pigment on chloroplasts in plants, which can achieve the precise controlled release of the model fungicide methylene blue (MB). The experimental results show that the biomimetic channels have good circularity after and before light conditions. In addition, it is also found that the release of MB in visible light by the retinal-modified channels is 8.78 µmol·m-2·h-1, which is four times higher than that in the before light conditions. Furthermore, MB, a bactericide drug model released under visible light, can effectively inhibit the growth of PA, reaching a 97% inhibition effect. The biomimetic nanochannels can realize the controlled release of the fungicide MB, which provides a new way for the treatment of PA on the leaves surface of cucumber, further expanding the application field of biomimetic nanomembrane carrier materials.

Recent Advances in Stimulus-Responsive Nanocarriers for Pesticide Delivery.

In an effort to make pesticide use safer, more efficient, and sustainable, micro-/nanocarriers are increasingly being utilized in agriculture to deliver pesticide-active agents, thereby reducing quantities and improving effectiveness. In the use of nanopesticides, the choice to further design and prepare pesticide stimulus-responsive nanocarriers based on changes in the plant growth environment (light, temperature, pH, enzymes, etc.) has received more and more attention from researchers. Based on this, this paper examines recent advancements in nanomaterials for the design of stimulus-responsive micro-/nanocarriers. It delves into the intricacies of preparation methods, material enhancements, in vivo/ex vivo controlled release, and application techniques for controlled release formulations. The aim is to provide a crucial reference for harnessing nanotechnology to pursue reduced pesticide use and increased efficiency.

Selectively Transport and Removal of Fluoride Ion by Pillar[5]Arene Polymer-Filled Nanochannel Membrane.

Excess fluoride ions in groundwater accumulate through the roots of crops, affecting photosynthesis and inhibiting their growth. Long-term bioaccumulation also threatens human health because it is poorly degradable and toxic. Currently, one of the biggest challenges is developing a unique material that can efficiently remove fluoride ions from the environment. The excellent properties of functionalized pillar[5]arene polymer-filled nanochannel membranes were explored to address this challenge. Constructing a multistage porous nanochannel membrane, consisting of microscale etched nanochannels and nanoscale pillar[5]arene cross-linked polymer voids. A fluoride removal rate of 0.0088 mmol ⋅ L-1 ⋅ min-1 was achieved. Notably, this rate surpassed the rates observed with other control ions by a factor of 6 to 8.8. Our research provides a new direction for developing water fluoride ion removal materials.

Cycl[2,2,4]azine-embedded non-alternant nanographenes containing fused antiaromatic azepine ring.

The development of non-alternant nanographenes has attracted considerable attention due to their unique photophysical properties. Herein, we reported a novel aza-doped, non-alternant nanographene (NG) 1 by embedding the cycl[2,2,4]azine unit into the benzenoid NG framework. Single-crystal X-ray diffractometry suggests saddle or twisted nonplanar geometry of the entire backbone of 1 and coplanar conformation of the cycl[2,2,4]azine unit. DFT calculation together with solid structure indicates that NG 1 possesses significant local antiaromaticity in the azepine ring. By oxidative process or trifluoroacetic acid treatment, this nanographene can transform into a mono-radical cation, which was confirmed by UV/Vis absorption, 1H NMR, and electron paramagnetic resonance (EPR) spectroscopy. The antiaromaticity/aromaticity switching of the azepine ring on 1˙+ from 1 enables the high stability of this radical cation, which remained intact for over 1 day. Due to the electron-donating nature of the nitrogen and the unique electronic structure, NG 1 exhibits strong electron-donating properties, as proved by the intermolecular charge transfer towards C60 with a high association constant. Furthermore, selective modification of NG 1 was accomplished by Vilsmeier reaction, and the derivatives 7 and 8 with substituted benzophenone were obtained. The photophysical and electronic properties can be tuned by the introduction of different electronic groups in benzophenone.

The Specific Removal of Perfluorooctanoic Acid Based on Pillar[5]arene-Polymer-Packed Nanochannel Membrane.

The conspicuous surface activity and exceptional chemical stability of perfluorooctanoic acid, commonly referred to as PFOA, have led to its extensive utilization across a broad spectrum of industrial and commercial products. Nonetheless, significant concerns have arisen regarding the environmental presence of PFOAs, driven by their recognized persistence, bioaccumulative nature, and potential human health risks. In the realm of sustainable agriculture, a pivotal challenge revolves around the development of specialized materials capable of effectively and selectively eliminating PFOA from the environment. This study proposes harnessing the exceptional properties of a pillar[5]arene polymer to construct a nanochannel membrane filled with tryptophan-alanine dipeptide pillar[5]arene polymer. Through the functionalization of these nanochannel membranes, we achieved a PFOA removal rate of 0.01 mmol L-1 min-1, surpassing the rates observed with other control chemicals by a factor of 4.5-15. The research on PFOA removal materials has been boosted because of the creation of this highly selective PFOA removal membrane.

Effect of built environment on BMI of older adults in regions of different socio-economic statuses.

Background: Numerous studies have ignored the influence of underdeveloped urban surroundings on the physical health of China's ageing population. Lanzhou is a typical representative of a less developed city in China. Methods: This study investigated the relationship between body mass index (BMI) and built environment amongst older adults in regions of different socio-economic statuses (SES) using data from medical examinations of older adults in Lanzhou, as well as calculating community built environment indicators for regions of different SES based on multiple linear regression models. Results: Results showed that age and underlying disease were negatively associated with overall older adult BMI in the study buffer zone. Land use mix, number of parks and streetscape greenery were positively associated with older adult BMI. Street design and distance to bus stops were negatively connected in low SES regions, but population density and street design were negatively correlated in high SES areas. Conclusion: These findings indicate that the built environment of SES regions has varying impacts on the BMI of older persons and that planners may establish strategies to lower the incidence of obesity amongst older adults in different SES locations.

Azepine-Embedded Seco-Hexabenzocoronene-Based Helix Nanographenes: Access to Modification of the Core by N-H Functionalization.

Contorted polycyclic aromatic hydrocarbons (PAHs) or nanographenes (NGs) have received increasing attention and are mostly prepared by "bottom-up" strategies. Apparently, systematically tuning the properties of NGs for application is important but challenging. Here, a new type of helix, azepine-embedded NGs, were designed and synthesized by the introduction of NH into the hexa-peri-hexabenzocoronene (HBC) core. We demonstrate that this nitrogen-doped NG can be functionalized via N-H derivatization. Through modifications to the NH site with a chiral auxiliary reagent, optical resolution of the chiral NG was achieved. Meanwhile, it was found that by introducing various aryl groups with electron-donating or electron-withdrawing substituents, the emission intensity and the fluorescence mechanism can be modulated. Compared to the original NH-containing NG, the modified derivative exhibited improved fluorescence efficiency and tunable emission wavelength. A functionalized structure of benzoic acid with considerably improved fluorescence efficiency, hydrophilicity, and membrane permeability to stain the live cells was proved.

Photolysis of the BODIPY dye activated by pillar[5]arene.

Here, a pseudo[3]rotaxane comprising a fluorescent BODIPY derivative and pillar[5]arene was conveniently fabricated via host-guest complexation. Importantly, in this system, the efficient photodecomposition of the BODIPY derivative in the presence of pillar[5]arene was witnessed upon irradiation at 311 nm light, which was demonstrated via UV-Vis absorption, fluorescence emission, NMR and HR-MS spectroscopy techniques, but the only BODIPY dye in the absence of pillar[5]arene couldn't undergo photodegradation. We demonstrated that pillar[5]arene could act as an activator to trigger the photodegradation reaction of BODIPY derivatives via free radical reactions even without supramolecular interactions. The present results provide a new strategy for the efficient photolysis of organic dyes.

A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation.

Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor - type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique "capture-for-degradation" mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions.

A universal combinatorial design of antibody framework to graft distinct CDR sequences: a bioinformatics approach.

Antibody (Ab) humanization is crucial to generate clinically relevant biologics from hybridoma-derived monoclonal antibodies (mAbs). In this study, we integrated antibody structural information from the Protein Data Bank with known back-to-mouse mutational data to build a universal consensus of framework positions (10 heavy and 7 light) critical for the preservation of the functional conformation of the Complimentarity Determining Region of antibodies. On the basis of FR consensus, we describe here a universal combinatorial library suitable for humanizing exogenous antibodies by CDR-grafting. The six CDRs of the murine anti-human EGFR Fab M225 were grafted onto a distinct (low FR sequence similarity to M225) human FR sequence that incorporates at the 17 FR consensus positions the permutations of the naturally observed amino acid diversities. Ten clones were selected from the combinatorial library expressing phage-displayed humanized M225 Fabs. Surprisingly, 2 of the 10 clones were found to bind EGFR with stronger affinity than M225. Cell-based assays demonstrated that the 10 selected clones retained epitope specificity by blocking EGFR phosphorylation and thus hindering cellular proliferation. Our results suggest that there is a universal and structurally rigid near-CDR set of FR positions that cooperatively support the binding conformation of CDRs.

Development of a fully human anti-PDGFRbeta antibody that suppresses growth of human tumor xenografts and enhances antitumor activity of an anti-VEGFR2 antibody.

Platelet-derived growth factor receptor beta (PDGFRbeta) is upregulated in most of solid tumors. It is expressed by pericytes/smooth muscle cells, fibroblast, macrophage, and certain tumor cells. Several PDGF receptor-related antagonists are being developed as potential antitumor agents and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here, we produced a fully human neutralizing antibody, IMC-2C5, directed against PDGFRbeta from an antibody phage display library. IMC-2C5 binds to both human and mouse PDGFRbeta and blocks PDGF-B from binding to the receptor. IMC-2C5 also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules in tumor cells. In animal studies, IMC-2C5 significantly delayed the growth of OVCAR-8 and NCI-H460 human tumor xenografts in nude mice but failed to show antitumor activities in OVCAR-5 and Caki-1 xenografts. Our results indicate that the antitumor efficacy of IMC-2C5 is primarily due to its effects on tumor stroma, rather than on tumor cells directly. Combination of IMC-2C5 and DC101, an anti-mouse vascular endothelial growth factor receptor 2 antibody, resulted in significantly enhanced antitumor activity in BxPC-3, NCI-H460, and HCT-116 xenografts, compared with DC101 alone, and the trend of additive effects to DC101 treatment in several other tumor models. ELISA analysis of NCI-H460 tumor homogenates showed that IMC-2C5 attenuated protein level of vascular endothelial growth factor and basic fibroblast growth factor elevated by DC101 treatment. Finally, IMC-2C5 showed a trend of additive effects when combined with DC101/chemotherapy in MIA-PaCa-2 and NCI-H460 models. Taken together, these results lend great support to the use of PDGFRbeta antagonists in combination with other antiangiogenic agents in the treatment of a broad range of human cancers.

Transcriptional expression of fljB:z66, a flagellin gene located on a novel linear plasmid of Salmonella enterica serovar Typhi under environmental stresses.

A previous study identified that z66+ strain of Salmonella enterica serovar Typhi contains two different flagellin genes, the fliC encoding d or j antigen in chromosome and the fljB-like gene encoding z66 antigen in a novel linear plasmid, respectively. The promoter of fljB:z66 is different from that of fliC:d/j and z66+ strain alters flagellin expression in only one orientation, from z66 to d orj antigen, raising the suspicion that z66+ strain is a special biphasic strain. To clarify the expressional characteristics of flagellin genes of z66+ strain, expression patterns of fljB:z66 and fliC were investigated by RT-PCR under a series of environmental stresses during infection, such as acidic stress, osmotic stress, bile acid stress and oxidative stress. Results showed that the expression level of fljB:z66 is over 10-fold higher than the level of fliC in low and middle osmotic conditions before stresses. Only the expressional regulatory tendency of fljB:z66 in response to bile acid stress is similar to that of fliC. Differential expressional patterns between fljB:z66 and fliC of S. enterica serovar Typhi were seen under osmotic stress, bile acid stress and oxidative stress. These results support the hypothesis that the z66+ strain is a special biphasic strain of S. enterica serovar Typhi.

An antibody directed against PDGF receptor beta enhances the antitumor and the anti-angiogenic activities of an anti-VEGF receptor 2 antibody.

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment and vessel maturation. Here we produced a neutralizing antibody, 1B3, directed against mouse PDGFRbeta. 1B3 binds to PDGFRbeta with high affinity (9x10(-11)M) and blocks PDGF-BB from binding to the receptor with an IC(50) of approximately 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of 1B3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFRbeta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.

Single variable domain antibody as a versatile building block for the construction of IgG-like bispecific antibodies.

Bispecific antibodies (BsAb) have been traditionally utilized to redirect cytotoxic effector cells and agents to kill tumor cells expressing the target antigens. Recently a new concept is emerging to develop BsAb that simultaneously block the functions of two tumor-associated targets, eg., growth factor receptors, for enhanced antitumor efficacies. Broad clinical applications of BsAb have been, and still are, significantly hampered by the difficulty in producing the materials in sufficient quantity and quality by traditional approaches. Here we describe a recombinant approach for the production of an Fc domain-containing, IgG-like tetravalent BsAb, using a single variable domain (sVD) antibody as a versatile building block. In this method, a sVD of a defined specificity is genetically fused to either the N-terminus of the light chain or the C-terminus of the heavy chain of a functional IgG antibody of a different specificity. A model BsAb was constructed using a sVD to mouse platelet derived growth factor receptor alpha and a conventional IgG antibody to mouse platelet derived growth factor receptor beta. The BsAb were expressed in mammalian cells and purified to homogeneity by a one-step Protein A affinity chromatography. Further, the BsAb retained the antigen binding specificity and the receptor neutralizing activity of both of its parent antibodies. Importantly, the BsAb inhibited the activation of both its target receptors in tumor cells stimulated by both platelet derived growth factor AA and BB, whereas the parent monospecific antibody only inhibited the activation of a single receptor stimulated by its cognate ligand. This format of BsAb should be readily applicable to the production of other BsAb recognizing any pairs of antigens.

Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2.

Compelling evidence suggest that vascular endothelial growth factor (VEGF) and its receptors, especially receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies such as age-related macular degeneration (AMD). To this end, inhibition of angiogenesis with antagonists to either VEGF or KDR has yielded significant therapeutic efficacy both in preclinical studies in animal models and in clinical trials in patients with cancer and AMD. We previously reported the identification of a high affinity, fully human anti-KDR antibody fragment, 1121B Fab, through a highly stringent affinity maturation process with a Fab originally isolated from a naïve human antibody phage display library. In this study, we demonstrate that 1121B Fab is able to strongly block KDR/VEGF interaction, resulting in potent inhibition of an array of biological activities of VEGF, including activation of the receptor and its signaling pathway, intracellular calcium mobilization, and migration and proliferation of endothelial cells. Taken together, our data lend strong support to the further development of 1121B Fab fragment as an anti-angiogenesis agent in both cancer and angiogenic retinopathies.

Single variable domain-IgG fusion. A novel recombinant approach to Fc domain-containing bispecific antibodies.

Both laboratory and early clinical studies to date have demonstrated that bispecific antibodies (BsAb) may have potentially significant application in cancer therapy. The clinical development of BsAb as therapeutics has been hampered, however, by the difficulty in preparing the materials in sufficient quantity and quality by traditional methods. In recent years, a variety of recombinant methods has been developed for efficient production of BsAb, both as antibody fragments and as full-length IgG-like molecules. Here we describe a novel recombinant approach for the production of an Fc domain-containing, IgG-like tetravalent BsAb, with two antigen-binding sites to each of its target antigens, by genetically fusing a single variable domain antibody to the N terminus of the light chain of a functional IgG antibody of different specificity. A model BsAb was constructed using a single variable domain antibody to mouse platelet-derived growth factor receptor alpha and a conventional IgG antibody to mouse vascular endothelial growth factor receptor 2. The BsAb was expressed in mammalian cells and purified to homogeneity by one-step protein A affinity chromatography. Furthermore, the BsAb retains the antigen binding specificity and the receptor neutralizing activity of both of its parent antibodies. This design and expression of Fc domain-containing, IgG-like BsAb should be applicable to the construction of similar BsAb from antibodies recognizing any pair of antigens.

A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity.

Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGFR) have been implicated in the tumorigenesis of a variety of cancers. Here we propose that simultaneous targeting of both receptors with a bispecific antibody would lead to enhanced antitumor activity. To this end, we produced a recombinant human IgG-like bispecific antibody, a Di-diabody, using the variable regions from two antagonistic antibodies: IMC-11F8 to EGFR and IMC-A12 to IGFR. The Di-diabody binds to both EGFR and IGFR and effectively blocked both EGF- and IGF-stimulated receptor activation and tumor cell proliferation. The Di-diabody also inherited the biological properties from both of its parent antibodies; it triggers rapid and significant IGFR internalization and degradation and mediates effective antibody-dependent cellular cytotoxicity in a variety of tumor cells. Finally, the Di-diabody strongly inhibited the growth of two different human tumor xenografts in vivo. Our results underscore the benefits of simultaneous targeting of two tumor targets with bispecific antibodies.

The molecular basis of tamoxifen induction of mouse uterine epithelial cell proliferation.

Tamoxifen, a selective estrogen modulator (SERM) that has found clinical utility in the treatment of breast cancer, is an antagonist in the breast and an agonist in the uterus. These agonist actions in the uterus lead to an increased risk of endometrial cancer. In this study in mice we have analyzed the mechanism of action of tamoxifen in inducing cell proliferation in the uterine luminal epithelia. Tamoxifen induces a wave of DNA synthesis in these epithelial cells with kinetics similar to those seen after 17beta-estradiol (E(2)) treatment. However, by these criteria of mitogenicity, it is much less potent and never achieves full estrogenicity. This uterine epithelial cell proliferation is preceded by the mobilization of cyclin D1 from the cytoplasm to the nucleus which, together with CDK4, phosphorylates members of the Rb-retinoblastoma family of proteins, pRb and p107. Subsequent to this initial nuclear accumulation of cyclin D1, cyclin E and then cyclin A are induced that, together with the activation of CDK2, results in enhanced cyclin E- and cyclin A-dependent CDK2 kinase activity and further phosphorylation of pRb and p107. These actions of tamoxifen parallel those of E(2). Tamoxifen also induced the classical estrogen water imbibition response. However, in this it was more potent, producing a maximal response at doses that do not affect DNA synthesis. This suggests that the uterotropic response is not an accurate predictor of the compound's hyperplasia responses. We can conclude that, in its effects on proliferation, tamoxifen acts as a classical impeded estrogen and this suggests that the AF-1 transcription activation domain of the estrogen receptor that is activated upon both E(2) and tamoxifen binding to this receptor regulates these responses in the uterus.

Inhibition of both the autocrine and the paracrine growth of human leukemia with a fully human antibody directed against vascular endothelial growth factor receptor 2.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. Here we show that certain "liquid" tumors such as acute myeloid leukemia not only produce VEGF but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. In addition, the leukemia-derived VEGF can also stimulate the production of growth factors, including interleukin 6 (IL6) and granulocyte-macrophage colony stimulating factor (GM-CSF), by human endothelial cells, which in turn further promotes the growth of leukemia cells (the paracrine loop). A fully human anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-2C6, strongly blocks KDR/VEGF interaction and neutralizes VEGF-stimulated activation of KDR in endothelial cells. In a system where leukemia cells are co-cultured with endothelial cells, IMC-2C6 inhibits both the production of IL6 and GM-CSF by endothelial cells and the growth of leukemia cells. Finally, IMC-2C6 effectively blocks VEGF-induced migration of KDR+ human leukemia cells, and when administered in vivo, significantly prolonged survival of mice inoculated with KDR+ human leukemia cells. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and certain types of leukemia.

Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody.

FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase, is expressed at high levels in the blasts of approximately 90% of patients with acute myelogenous leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and point mutations in the kinase domain of FLT3 are found in approximately 37% of AML patients and are associated with a poor prognosis. We report here the development and characterization of a fully human anti-FLT3 neutralizing antibody (IMC-EB10) isolated from a human Fab phage display library. IMCEB10 (immunoglobulin G1 [IgG1], kappa) binds with high affinity (KD=158 pM) to soluble FLT3 in enzyme-linked immunosorbent assay (ELISA) and to FLT3 receptor expressed on the surfaces of human leukemia cell lines. IMC-EB10 blocks the binding of FLT3 ligand (FL) to soluble FLT3 in ELISA and competes with FL for binding to cell-surface FLT3 receptor. IMC-EB10 treatment inhibits FL-induced phosphorylation of FLT3 in EOL-1 and EM3 leukemia cells and FL-independent constitutive activation of ITD-mutant FLT3 in BaF3-ITD and MV4;11 cells. Activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and AKT is also inhibited in these cell lines by antibody treatment. The antibody inhibits FL-stimulated proliferation of EOL-1 cells and ligand-independent proliferation of BaF3-ITD cells. In both EOL-1 xenograft and BaF3-ITD leukemia models, treatment with IMC-EB10 significantly prolongs the survival of leukemia-bearing mice. No overt toxicity is observed with IMC-EB10 treatment. Taken together, these data demonstrate that IMC-EB10 is a specific and potent inhibitor of wild-type and ITD-mutant FLT3 and that it deserves further study for targeted therapy of human AML.