title: Toward experimental assessment of receptor occupancy: TGN1412 revisited.
abstract: In March 2006, 6 healthy volunteers experienced serious adverse reactions during a first-in-human clinical trial of the superagonistic anti-CD28 mAb TGN1412. A first investigation excluded contaminations of the drug product or protocol irregularities as the root cause. Later, an expert scientific group convened in the United Kingdom to develop recommendations pertinent to minimizing risks of first-in-human clinical trials. The expert scientific group concluded from in silico calculations that at the initial dose of 0.1 mg/kg, which was adjusted on the basis of the no observed adverse effect level, approximately 86.2% to 90.9% CD28 receptor occupancy was obtained. Here we developed a flow cytometric method that revealed receptor occupancy of approximately 45% to 80% under the above conditions. Thus we present a method to experimentally determine receptor occupancy that can be taken as one parameter to define the minimal anticipated biological effect level as the basis for calculating safer starting doses for first-in-human clinical trials for products in which a potential risk has been identified. Additional measures are being discussed that will help to significantly improve safety of first-in-human clinical trials.
authors.affiliation: Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
authors.forename: Linda Y
authors.initials: LY
authors.lastname: Sender
authors.forename: Christel
authors.initials: C
authors.lastname: Kamp
authors.forename: Jan
authors.initials: J
authors.lastname: Müller-Berghaus
authors.forename: Bernd
authors.initials: B
authors.lastname: Liedert
authors.forename: Christian K
authors.initials: CK
authors.lastname: Schneider
authors.forename: Johannes
authors.initials: J
authors.lastname: Löwer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005434:Flow Cytometry; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D011971:Receptors, Immunologic / Q000276:immunology*; D018675:Toxicity Tests
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D011971:Receptors, Immunologic; C509303:TGN-1412