title: Human microtubule-associated protein tau mediates targeted killing of CD30(+) lymphoma cells in vitro and inhibits tumour growth in vivo.
abstract: Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) are rare lymphoproliferative cancer types. Although most HL patients can be cured by chemo- and radio-therapy, 4-50% of patients relapse and have a poor prognosis. The need for improved therapeutic options for patients with relapsed or refractory disease has been addressed by CD30-specific antibody-based immunotherapeutics. However, available CD30-specific monoclonal antibodies (mAbs), antibody drug conjugates (ADCs) or chimeric immunotoxins suffer from the requirement of a functional host immunity, undesirable immune reactions or heterogeneity and instability, respectively. Here, we present a new fusion protein comprised of the CD30-specific antibody single-chain fragment Ki4(scFv) and the human pro-apoptotic effector protein, microtubule-associated protein tau (MAPT). Ki4(scFv)-MAP selectively induced apoptosis in rapidly proliferating L540cy, L428, and Karpas 299 cells in a dose-dependent manner. Tubulin polymerization assays confirmed that Ki4(scFv)-MAP stabilizes microtubules, suggesting a mechanism for its pro-apoptotic action. Dose-finding experiments proved that Ki4(scFv)-MAP is well tolerated in mice compared to the previously reported Ki4(scFv)-ETA'. Ki4(scFv)-MAP significantly inhibited growth of subcutaneous L540cy xenograft tumours in mice. Our data present a novel approach for the treatment of CD30(+) lymphomas, combining the binding specificity of a target-specific antibody fragment with the selective cytotoxicity of MAPT towards proliferating lymphoma cells.
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Dmitrij
authors.initials: D
authors.lastname: Hristodorov
authors.forename: Johannes
authors.initials: J
authors.lastname: Nordlohne
authors.forename: Radoslav
authors.initials: R
authors.lastname: Mladenov
authors.forename: Michael
authors.initials: M
authors.lastname: Huhn
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.forename: Theo
authors.initials: T
authors.lastname: Thepen
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D017730:Ki-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D017730:Ki-1 Antigen; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D016875:tau Proteins
keywords: CD30; Ki4; cytolytic fusion proteins; immunotherapy; lymphoma