Browsing by Author "Tian, Zeru"

Now showing 1 - 5 of 5
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    Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone
    (American Chemical Society, 2022) Tian, Zeru; Yu, Chenfei; Zhang, Weijie; Wu, Kuan-Lin; Wang, Chenhang; Gupta, Ruchi; Xu, Zhan; Wu, Ling; Chen, Yuda; Zhang, Xiang H.-F.; Xiao, Han; Bioengineering; Biosciences; Chemistry
    Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in the treatment of bone tumors is hampered due to the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies with bone-homing peptide sequences dramatically enhances their concentrations in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of bone-homing peptides into permissive sites of the anti-HER2 antibody, trastuzumab. Compared to the unmodified antibody, the engineered antibodies have similar pharmacokinetics and in vitro cytotoxic activity, but exhibit improved bone tumor distribution in vivo. Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multiorgan metastases. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody–drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust bone tumor delivery efficacy. This provides a powerful strategy to overcome the poor accessibility of antibodies to the bone tumors and the consequential resistance to the therapy.
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    Harnessing the power of antibodies to fight bone metastasis
    (AAAS, 2021) Tian, Zeru; Wu, Ling; Yu, Chenfei; Chen, Yuda; Xu, Zhan; Bado, Igor; Loredo, Axel; Wang, Lushun; Wang, Hai; Wu, Kuan-Lin; Zhang, Weijie; Zhang, Xiang H.-F.; Xiao, Han; Bioengineering; Biosciences; Chemistry
    Antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone microenvironment has proved to be difficult due to the relatively low vascularization of bone tissue and the presence of physical barriers. Here, we have used an innovative bone-targeting (BonTarg) technology to generate a first-in-class bone-targeting antibody. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to therapeutic antibodies. Bisphosphonate modification of these antibodies results in the delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In xenograft mice models, this strategy provides enhanced inhibition of bone metastases and multiorgan secondary metastases that arise from bone lesions. Specific delivery of therapeutic antibodies to the bone, therefore, represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases. Precision modification of antibodies with bone-targeting moieties unleashes their potential for the treatment of bone metastases. Precision modification of antibodies with bone-targeting moieties unleashes their potential for the treatment of bone metastases.
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    Oxime as a general photocage for the design of visible light photo-activatable fluorophores
    (Royal Society of Chemistry, 2021) Wang, Lushun; Wang, Shichao; Tang, Juan; Espinoza, Vanessa B.; Loredo, Axel; Tian, Zeru; Weisman, R. Bruce; Xiao, Han; Bioengineering; Biosciences; Chemistry
    Photoactivatable fluorophores have been widely used for tracking molecular and cellular dynamics with subdiffraction resolution. In this work, we have prepared a series of photoactivatable probes using the oxime moiety as a new class of photolabile caging group in which the photoactivation process is mediated by a highly efficient photodeoximation reaction. Incorporation of the oxime caging group into fluorophores results in loss of fluorescence. Upon light irradiation in the presence of air, the oxime-caged fluorophores are oxidized to their carbonyl derivatives, restoring strong fluorophore fluorescence. To demonstrate the utility of these oxime-caged fluorophores, we have created probes that target different organelles for live-cell confocal imaging. We also carried out photoactivated localization microscopy (PALM) imaging under physiological conditions using low-power light activation in the absence of cytotoxic additives. Our studies show that oximes represent a new class of visible-light photocages that can be widely used for cellular imaging, sensing, and photo-controlled molecular release.
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    Synthesis of precision antibody conjugates using proximity-induced chemistry
    (Ivyspring, 2021) Cao, Yu J.; Yu, Chenfei; Wu, Kuan-Lin; Wang, Xuechun; Liu, Dong; Tian, Zeru; Zhao, Lijun; Qi, Xuexiu; Loredo, Axel; Chung, Anna; Xiao, Han; Bioengineering; Biosciences; Chemistry
    Rationale: Therapeutic antibody conjugates allow for the specific delivery of cytotoxic agents or immune cells to tumors, thus enhancing the antitumor activity of these agents and minimizing adverse systemic effects. Most current antibody conjugates are prepared by nonspecific modification of antibody cysteine or lysine residues, inevitably resulting in the generation of heterogeneous conjugates with limited therapeutic efficacies. Traditional strategies to prepare homogeneous antibody conjugates require antibody engineering or chemical/enzymatic treatments, processes that often affect antibody folding and stability, as well as yield and cost. Developing a simple and cost-effective way to precisely couple functional payloads to native antibodies is of great importance. Methods: We describe a simple proximity-induced antibody conjugation method (pClick) that enables the synthesis of homogeneous antibody conjugates from native antibodies without requiring additional antibody engineering or post-synthesis treatments. A proximity-activated crosslinker is introduced into a chemically synthesized affinity peptide modified with a bioorthogonal handle. Upon binding to a specific antibody site, the affinity peptide covalently attaches to the antibody via spontaneous crosslinking, yielding an antibody molecule ready for bioorthogonal conjugation with payloads. Results: We have prepared well-defined antibody-drug conjugates and bispecific small molecule-antibody conjugates using pClick technology. The resulting conjugates exhibit excellent in vitro cytotoxic activity against cancer cells and, in the case of bispecific conjugates, superb antitumor activity in mouse xenograft models. Conclusions: Our pClick technology enables efficient, simple, and site-specific conjugation of various moieties to the existing native antibodies. This technology does not require antibody engineering or additional UV/chemical/enzymatic treatments, therefore providing a general, convenient strategy for developing novel antibody conjugates.
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    Unleashing the potential of noncanonical amino acid biosynthesis to create cells with precision tyrosine sulfation
    (Springer Nature, 2022) Chen, Yuda; Jin, Shikai; Zhang, Mengxi; Hu, Yu; Wu, Kuan-Lin; Chung, Anna; Wang, Shichao; Tian, Zeru; Wang, Yixian; Wolynes, Peter G.; Xiao, Han; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological Physics
    Despite the great promise of genetic code expansion technology to modulate structures and functions of proteins, external addition of ncAAs is required in most cases and it often limits the utility of genetic code expansion technology, especially to noncanonical amino acids (ncAAs) with poor membrane internalization. Here, we report the creation of autonomous cells, both prokaryotic and eukaryotic, with the ability to biosynthesize and genetically encode sulfotyrosine (sTyr), an important protein post-translational modification with low membrane permeability. These engineered cells can produce site-specifically sulfated proteins at a higher yield than cells fed exogenously with the highest level of sTyr reported in the literature. We use these autonomous cells to prepare highly potent thrombin inhibitors with site-specific sulfation. By enhancing ncAA incorporation efficiency, this added ability of cells to biosynthesize ncAAs and genetically incorporate them into proteins greatly extends the utility of genetic code expansion methods.