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  1. Article ; Online: N-terminal selective conjugation method widens the therapeutic window of antibody-drug conjugates by improving tolerability and stability.

    Ko, Min Ji / Song, Daehae / Kim, Juhee / Kim, Jae Yong / Eom, Jaehyun / Sung, Byungje / Son, Yong-Gyu / Kim, Young Min / Lee, Sang Hoon / You, Weon-Kyoo / Jung, Jinwon

    mAbs

    2021  Volume 13, Issue 1, Page(s) 1914885

    Abstract: Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and ...

    Abstract Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable
    MeSH term(s) Alkylation ; Animals ; Antineoplastic Agents, Immunological/chemistry ; Antineoplastic Agents, Immunological/pharmacokinetics ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/toxicity ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Drug Compounding ; Drug Stability ; Female ; Immunoconjugates/chemistry ; Immunoconjugates/pharmacokinetics ; Immunoconjugates/pharmacology ; Immunoconjugates/toxicity ; Oligopeptides/chemistry ; Oligopeptides/pharmacokinetics ; Oligopeptides/pharmacology ; Oligopeptides/toxicity ; Protein Stability ; Rats, Nude ; Rats, Sprague-Dawley ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Trastuzumab/chemistry ; Trastuzumab/pharmacokinetics ; Trastuzumab/pharmacology ; Trastuzumab/toxicity ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; Rats
    Chemical Substances Antineoplastic Agents, Immunological ; Immunoconjugates ; Oligopeptides ; monomethylauristatin F ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
    Language English
    Publishing date 2021-04-27
    Publishing country United States
    Document type Comparative Study ; Journal Article
    ZDB-ID 2537838-7
    ISSN 1942-0870 ; 1942-0870
    ISSN (online) 1942-0870
    ISSN 1942-0870
    DOI 10.1080/19420862.2021.1914885
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier.

    Shin, Jung-Won / An, Sungwon / Kim, Dongin / Kim, Hyunjoo / Ahn, Jinhyung / Eom, Jaehyun / You, Weon-Kyoo / Yun, Hyesu / Lee, Bora / Sung, Byungje / Jung, Jinwon / Kim, Sehyun / Son, Yonggyu / Sung, Eunsil / Lee, Hanbyul / Lee, Suyeon / Song, Daehae / Pak, Youngdon / Sandhu, Jagdeep K /
    Haqqani, Arsalan S / Stanimirovic, Danica B / Yoo, Jiseon / Kim, Donghwan / Maeng, Sungho / Lee, Jeonghun / Lee, Sang Hoon

    Cell reports methods

    2022  Volume 2, Issue 11, Page(s) 100338

    Abstract: Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular ... ...

    Abstract Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here, we report insulin-like growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. We also describe Grabody B, an antibody against IGF1R, as a molecular shuttle. Grabody B has broad cross-species reactivity and does not interfere with IGF1R-mediated signaling. We demonstrate that administration of Grabody B-fused anti-alpha-synuclein (α-Syn) antibody induces better improvement in neuropathology and behavior in a Parkinson's disease animal model than the therapeutic antibody alone due to its superior serum pharmacokinetics and enhanced brain exposure. The results indicate that IGF1R is an ideal shuttle target and Grabody B is a safe and efficient molecular shuttle.
    MeSH term(s) Animals ; Blood-Brain Barrier/metabolism ; Biological Products/metabolism ; Endothelial Cells/metabolism ; Brain/metabolism ; Biological Transport ; Antibodies/metabolism
    Chemical Substances Biological Products ; Antibodies
    Language English
    Publishing date 2022-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2667-2375
    ISSN (online) 2667-2375
    DOI 10.1016/j.crmeth.2022.100338
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8

    You, Gihoon / Lee, Yangsoon / Kang, Yeon-Woo / Park, Han Wook / Park, Kyeongsu / Kim, Hyekang / Kim, Young-Min / Kim, Sora / Kim, Ji-Hae / Moon, Dain / Chung, Hyejin / Son, Wonjun / Jung, Ui-Jung / Park, Eunyoung / Lee, Shinai / Son, Yong-Gyu / Eom, Jaehyun / Won, Jonghwa / Park, Yunji /
    Jung, Jaeho / Lee, Seung-Woo

    Science advances

    2021  Volume 7, Issue 3

    Abstract: Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4- ... ...

    Abstract Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1
    MeSH term(s) Animals ; Antibodies, Bispecific/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice ; Neoplasms/drug therapy ; Programmed Cell Death 1 Receptor
    Chemical Substances Antibodies, Bispecific ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2021-01-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.aax3160
    Database MEDical Literature Analysis and Retrieval System OnLINE

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