Author: Cyr, Matthew G ; Rader, Christoph ; Herrick, John ; Griffin, Patrick R ; Wiestner, Adrian ; Gaglione, Erika M ; Chang, Jing ; Mhibik, Maissa ; Novick, Scott J ; Courouble, Valentine V ; Venables, Thomas ; Qi, Junpeng ; Eik, David ; Peng, Haiyong

BackgroundDespite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the anti-CD20 monoclonal antibody (mAb) rituximab is the elimination of all healthy B cells, resulting in impaired humoral immunity. We previously reported the identification of a patient-derived, CLL-binding mAb, JML-1, and identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) as the target of JML-1. Although little is known about Siglec-6, it appears to be an attractive target for cancer immunotherapy due to its absence on most healthy cells and tissues.MethodsWe used a target-specific approach to mine for additional patient-derived anti-Siglec-6 mAbs. To assess the therapeutic utility of targeting Siglec-6 in the context of CLL, T cell-recruiting bispecific antibodies (T-biAbs) that bind to Siglec-6 and CD3 were engineered into single-chain variable fragment–Fc and dual-affinity retargeting (DART)–Fc constructs. T-biAbs were evaluated for their activity in vitro, ex vivo, and in vivo.ResultsWe discovered the anti-Siglec-6 mAbs RC-1 and RC-2, which bind with higher affinity than JML-1 yet maintain similar specificity. Both JML-1 and RC-1 T-biAbs were effective at activating T cells and killing Siglec-6+target cells. The RC-1 clone in the DART–Fc format was the most potent T-biAb tested and was the only anti-Siglec-6 T-biAb that eliminated Siglec-6+primary CLL cells via autologous T cells at pathological T-to-CLL cell ratios. Tested at healthy T-to-B cell ratios, it also eliminated a Siglec-6+fraction of primary B cells from healthy donors. The subpicomolar potency of the DART–Fc format was attributed to the reduction in the length and flexibility of the cytolytic synapse. Furthermore, the RC-1 T-biAb was effective at clearing MEC1 CLL cells in vivo and demonstrated a circulatory half-life of over 7 days.ConclusionSiglec-6-targeting T-biAbs are highly potent and specific for eliminating Siglec-6+leukemic and healthy B cells while sparing Siglec-6−healthy B cells, suggesting a unique treatment strategy for CLL with diminished suppression of humoral immunity. Our data corroborate reports that T-biAb efficacy is dependent on synapse geometry and reveal that synapse architecture can be tuned via antibody engineering. Our fully human anti-Siglec-6 antibodies and T-biAbs have potential for cancer immunotherapy.Trial registration numberNCT00923507.

04 Sep 2018·Inorganic ChemistryQ2 · CHEMISTRY

Click Chemistry-Assisted Synthesis of a β-d-Galactose-Targeted SiO₂@RC Shell–Core Structure as a Nanoplatform for Metal-Based Complex Delivery

Q2 · CHEMISTRY

Article

Author: Hu, Fan ; Shuai, Qi ; Xu, Xiuling

A facile reversed-phase microemulsion method was used to synthesize shell-core nanospheres of SiO₂@RCs (SiO₂-encapsuled rare-earth metal complexes). β-d-Galactose was then grafted onto the surfaces of the nanospheres through the copper(I)-catalyzed azide-alkyne cycloaddition click reaction for targeted delivery. The chemical characteristics and surface profiles of the nanocarriers were investigated by Fourier transform infrared spectroscopy, dynamic light scattering, transmission electron microscopy, and scanning electron microscopy. A high-efficiency microwave synthesis method was applied to prepare five complex cores by the reaction of different rare-earth metal salts with two isomeric ligands, o-CPA (2-chlorophenoxyacetic acid) and m-CPA (3-chlorophenoxyacetic acid). The crystal structures of the five synthesized RC cores were confirmed through X-ray diffraction, which revealed the formulas of five RCs, [Dy( o-CPA)₃(H₂O)]·H₂O RC₁, [Ho( o-CPA)₃(H₂O)]·H₂O RC₂, 2[Er( m-CPA)₃(H₂O)]·3H₂O RC₃, 2[Gd( m-CPA)₃(H₂O)]·3H₂O RC₄, and [Ce₂( m-CPA)₆(H₂O)₃]·2H₂O RC₅. An in vitro cell study revealed that all RCs exhibited certain anticancer activities. RC₂, in particular, showed the strongest cytotoxicity against HepG2 cells. The enhanced cell permeability and drug retention considerably improved the cytotoxicity of all SiO₂@RC₂-gal relative to that of RC₂. The selective uptake of the β-d-galactose-conjugated nanospheres by HepG2 cells through mechanisms mediated by cell surface receptors resulted in fewer side effects on extrahepatic tissues. Our contribution provides a novel design concept of a target SiO₂@RCs-gal nanocarrier for delivering affordable antitumor complexes in cancer therapy.

01 May 2008·Journal of EthnopharmacologyQ2 · MEDICINE

Anti-HIV-1 activities of compounds isolated from the medicinal plant Rhus chinensis

Q2 · MEDICINE

Article

Author: Qiong Gu ; Liu-Meng Yang ; Rui-Rui Wang ; Yun-Hua Wang ; Yong-Tang Zheng ; Xue-Mei Zhang ; Ji-Jun Chen ; Jun Zhou

AIM OF THE STUDYPreviously, we reported that the petroleum ether fraction, RC-1, and EtOAc fraction, RC-2, of the medicinal plant Rhus chinensis showed potent anti-HIV-1 activities. To address anti-HIV-1 constituents of RC-1 and RC-2, 17 compounds were isolated. Anti-HIV-1 activities and possible action mechanisms of these compounds were investigated.METHODSThe syncytial formation induced by HIV-1 was determined under the inverted microscope, cellular toxicity and protection assay were assessed by MTT method, reduction of p24 antigen expression level and RT activity were measured by ELISA, and inhibition of recombinant HIV-1 PR was monitored by the fluorescent signal.RESULTSThe compounds 1 and 13 inhibited HIV-1-induced syncytium formation potently with TI value of 42.31 and 19.07, respectively. Compounds 4, 5, 6, 9 and 10 were less potent with TI value of 8.94, 8.22, 4.14, 5.11 and 5.34, respectively. Compound 1, a benzofuranone-type compound, previously reported as a novel anti-HIV-1 agent, might target late-steps of HIV-1 life cycle. Compound 13 inhibited HIV-1 replication with EC(50) of 7.16mug/ml and might target at/before integration step.CONCLUSIONThese compounds might contribute to anti-HIV-1 activities extracts of the medicinal plant Rhus chinensis.

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