title: CD30 as a therapeutic target for lymphoma.
abstract: Hodgkin's lymphoma (HL) and ALK(+) anaplastic large-cell lymphoma (ALCL) have become highly curable due to the success of modern regimens of chemotherapy and radiotherapy. However, up to one-third of the patients experience relapse or do not respond to first-line therapy, and half of them relapse again after secondary therapy with limited options for further treatment. In the last 15 years, monoclonal antibodies (mAbs) directed to surface receptors became a new and valuable therapeutic option in many hematologic malignancies. Due to its restricted expression on normal activated lymphocytes and its high expression on malignant cells, CD30 represents an attractive target molecule for HL and ALCL therapy. However, unconjugated CD30 mAbs have demonstrated a lack of objective clinical responses in patients with recurrent HL. CD30 exhibits complex signaling pathways, and binding of its natural ligand or anti-CD30 mAbs can induce apoptosis but may also promote proliferation and activation depending on the cellular context. Moreover, CD30 rapidly internalizes after crosslinking, which counteracts efficient recruitment of immunologic effectors but also provides the opportunity to transfer cytotoxic payloads coupled to CD30-specific mAbs into the tumor cells. Several tumor targeting approaches have been studied, including radio-immunoconjugates, immunotoxins, immunoRNases, immunokinases, and antibody drug conjugates (ADCs). In 2011, the ADC brentuximab-vedotin, consisting of the CD30-specific chimeric mAb cAC10 and the potent tubulin toxin monomethyl auristatin E, gained regulatory approval as a well tolerated and highly active drug in patients with refractory and relapsed HL and ALCL. SGN-35 is on the way to being incorporated in the standard management of CD30(+) lymphoma with significant therapeutic impact. This review gives a critical overview about anti-CD30 therapies with unconjugated, engineered, and conjugated mAbs and the therapeutic challenges of treatment of CD30(+) lymphoma.
authors.affiliation: Department of Biotechnology, Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany, th.schirrmann@tu-bs.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schirrmann
authors.forename: Miriam
authors.initials: M
authors.lastname: Steinwand
authors.forename: Xenia
authors.initials: X
authors.lastname: Wezler
authors.forename: Andre
authors.initials: A
authors.lastname: Ten Haaf
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Tur
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D017730:Ki-1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D058990:Molecular Targeted Therapy; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017730:Ki-1 Antigen; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases