Dataset Information

Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats.

ABSTRACT: As the current biotherapeutic market is dominated by antibodies, the design of different antibody formats, like bispecific antibodies and other new formats, represent a key component in advancing antibody therapy. When designing new formats, a targeted modulation of pairing preferences is key. Several existing approaches are successful, but expanding the repertoire of design possibilities would be desirable. Cognate immunoglobulin G antibodies depend on homodimerization of the fragment crystallizable regions of two identical heavy chains. By modifying the dimeric interface of the third constant domain (C_H3-C_H3), with different mutations on each domain, the engineered Fc fragments form rather heterodimers than homodimers. The first constant domain (C_H1-C_L) shares a very similar fold and interdomain orientation with the C_H3-C_H3 dimer. Thus, numerous well-established design efforts for C_H3-C_H3 interfaces, have also been applied to C_H1-C_L dimers to reduce the number of mispairings in the Fabs. Given the high structural similarity of the C_H3-C_H3 and C_H1-C_L domains we want to identify additional opportunities in comparing the differences and overlapping interaction profiles. Our vision is to facilitate a toolkit that allows for the interchangeable usage of different design tools from crosslinking the knowledge between these two interface types. As a starting point, here, we use classical molecular dynamics simulations to identify differences of the C_H3-C_H3 and C_H1-C_L interfaces and already find unexpected features of these interfaces shedding new light on possible design variations. Apart from identifying clear differences between the similar C_H3-C_H3 and C_H1-C_L dimers, we structurally characterize the effects of point-mutations in the C_H3-C_H3 interface on the respective dynamics and interface interaction patterns. Thus, this study has broad implications in the field of antibody engineering as it provides a structural and mechanistical understanding of antibody interfaces and thereby presents a crucial aspect for the design of bispecific antibodies.

SUBMITTER: Fernandez-Quintero ML

PROVIDER: S-EPMC8826573 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats.

Fernández-Quintero Monica L ML Quoika Patrick K PK Wedl Florian S FS Seidler Clarissa A CA Kroell Katharina B KB Loeffler Johannes R JR Pomarici Nancy D ND Hoerschinger Valentin J VJ Bujotzek Alexander A Georges Guy G Kettenberger Hubert H Liedl Klaus R KR

Frontiers in molecular biosciences 20220126

As the current biotherapeutic market is dominated by antibodies, the design of different antibody formats, like bispecific antibodies and other new formats, represent a key component in advancing antibody therapy. When designing new formats, a targeted modulation of pairing preferences is key. Several existing approaches are successful, but expanding the repertoire of design possibilities would be desirable. Cognate immunoglobulin G antibodies depend on homodimerization of the fragment crystalli ...[more]

PMID: 35155578

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Project description:BackgroundDispensed prescription medicine labels (prescription labels) are important information sources supporting safe and appropriate medicines use.ObjectiveTo develop and user test patient-centred prescription label formats.MethodsFive stages: developing 12 labels for four fictitious medicines of varying dosage forms; diagnostic user testing of labels (Round 1) with 40 consumers (each testing three labels); iterative label revision, and development of Round 2 labels (n = 7); user testing of labels (Round 2) with 20 consumers (each testing four labels); labelling recommendations. Evaluated labels stated the active ingredient and brand name, using various design features (eg upper case and bold). Dosing was expressed differently across labels: frequency of doses/day, approximate times of day (eg morning), explicit times (eg 7 to 9 AM), and/or explicit dosing interval. Participants' ability to find and understand medicines information and plan a dosing schedule were assessed.ResultsParticipants demonstrated satisfactory ability to find and understand the dosage for all label formats. Excluding active ingredient and dosing schedule, 14/19 labels (8/12 in Round 1; 6/7 in Round 2) met industry standard on performance. Participants' ability to correctly identify the active ingredient varied, with clear medicine name sign-posting enabling all participants evaluating these labels to find and understand the active ingredient. When planning a dosing schedule, doses were correctly spaced if the label stated a dosing interval, or frequency of doses/day. Two-thirds planned appropriate dosing schedules using a dosing table.ConclusionsEffective prescription label formatting and sign-posting of active ingredient improved communication of information on labels, potentially supporting safe medicines use.Patient and public involvementConsumers actively contributed to the development of dispensed prescription medicine labels. Feedback from consumers following the first round was incorporated in revisions of the labels for the next round. Patient and public involvement in this study was critical to the development of readable and understandable dispensed prescription medicine labels.

Dataset Information

Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats.

Publications

Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats.

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