Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains. The method can be applied across Igs to design Fc heterodimers and bsAbs. We investigated interfaces from human IgA CH3, IgD CH3, IgG1 CH3, IgM CH4, T-cell receptor (TCR) α/β, and TCR γ/δ constant domain pairs, and we found that they successfully drive human IgG1 CH3 or IgM CH4 heterodimerization to levels similar to or above those of reference methods. A comprehensive interface exchange between the TCR α/β constant domain pair and the IgG1 CH3 homodimer was evidenced by X-ray crystallography and used to engineer examples of bsAbs for cancer therapy. Parental antibody pairs were rapidly reformatted into scalable bsAbs that were free of homodimer traces by combining interface exchange, asymmetric Protein A binding, and the scFv × Fab format. In summary, we successfully built several new CH3- or CH4-based heterodimers that may prove useful for designing new bsAb-based therapeutics, and we anticipate that our approach could be broadly implemented across the Ig constant domain family. To our knowledge, CH4-based heterodimers have not been previously reported.
Tris and methanol have been used quite extensively as probes for surface-bound hydroxyl radicals in heterogeneous systems, such as TiO2 photocatalysis and catalytic decomposition of H2O2. Recent studies have indicated that the selectivity for surface-bound hydroxyl radicals is questionable and that the yield of the stable detectable product, formaldehyde, may be different for different reactive species. In this work, we have explored the selectivity as well as the formaldehyde yield of these two probes by experimentally studying formaldehyde formation in homogeneous (gamma radiolysis) and heterogeneous (TiO2 photocatalysis) systems, where hydroxyl radicals and Br2 · – can be formed. The latter is formed in the reaction between hydroxyl radicals and Br– at relatively high concentrations of Br–. The experiments clearly show that the formaldehyde yield is reduced by 85% when comparing hydroxyl radicals and Br2 · – in a homogeneous methanol system and increased by 50% when making the same comparison for the homogeneous Tris system. The increased yield is attributed to a change in the reaction mechanism as Br2 · – is mainly expected to produce a nitrogen-centered radical cation, while the hydroxyl radical mainly produces carbon-centered radicals. The radical cation appears to produce formaldehyde with a higher yield. In the photocatalysis system, the trends are similar but even more emphasized. The rationale for this is discussed, as well as the suitability of methanol and Tris as probes for surface-bound hydroxyl radicals in heterogeneous systems.
Kåre I. Birkeland er spesialist i indremedisin og i endokrinologi, professor ved Universitetet i Oslo og overlege ved Nyreseksjonen, Oslo universitetssykehus, Rikshospitalet. Han ledet arbeidet rundt blodsukkersenkende behandling i nasjonal faglig retningslinje for diabetes i Helsedirektoratet og leder Diabetesforbundets medisinske fagråd. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Han har holdt foredrag og ledet møter for firmaer som markedsfører utstyr og medikamenter til diabetesbehandling, som Astra Zeneca, Boehringer Ingelheim, Lilly, Merck, Novo Nordisk, Roche og Sanofi, med honorar til arbeidsgiver og bruk til egen forskning. Han mo ar honorar for å lede medisinsk fagråd i Diabetesforbundet.Sondre Meling er spesialist i indremedisin og i endokrinologi, overlege ved Endokrinologisk seksjon, Stavanger universitetssjukehus, stipendiat ved Universitetet i Bergen og leder for Norsk endokrinologisk forenings interessegruppe for diabetes, fedme og metabolisme. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Han har mo a honorar for møteledelse og foredrag for flere firma som markedsfører utstyr og medikamenter til diabetesbehandling, som Lilly, Novo Nordisk, Boehringer Ingelheim og Sanofi.Ingvild Va en Alsnes er spesialist i allmennmedisin og fastlege i Sandnes. Hun er førsteamanuensis ved Universitetet i Stavanger, styremedlem i Norsk forening for allmennmedisin og medlem av forskningsutvalget i Legeforeningen. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter.Emelie Svensson er lege i spesialisering i allmennmedisin, fastlege i Alta, fagansvarlig for Alta overgrepsmo ak, Finnmarkssykehuset og medlem av Diabetesforbundets medisinske fagråd. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter.Lars Gullestad er spesialist i indremedisin og i hjertesykdommer, overlege ved Hjertemedisinsk avdeling, Oslo universitetssykehus, Rikshospitalet og professor emeritus ved Universitetet i Oslo. Forfa eren har fylt ut ICMJE-skjemaet og oppgir følgende interessekonflikter: Han har mo a honorar for foredrag for flere firma som markedsfører medikamenter til diabetesbehandling, som Boheringer Ingelheim, AstraZeneca og MSD.Nye internasjonale anbefalinger for type 2-diabetes -hva gjør vi i Norge? | Tidsskrift for Den norske legeforening
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