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Design and engineering of deimmunized biotherapeutics.

ABSTRACT: Therapeutic proteins are powerful next-generation drugs able to effectively treat diverse and devastating diseases, but the development and use of biotherapeutics entails unique challenges and risks. In particular, protein drugs are subject to immune surveillance in the human body, and ensuing antidrug immune responses can cause a wide range of problems including altered pharmacokinetics, loss of efficacy, and even life-threating complications. Here we review recent progress in technologies for engineering deimmunized biotherapeutics, placing particular emphasis on deletion of immunogenic antibody and T cell epitopes via experimentally or computationally guided mutagenesis.

SUBMITTER: Griswold KE

PROVIDER: S-EPMC5067179 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Design and engineering of deimmunized biotherapeutics.

Griswold Karl E KE Bailey-Kellogg Chris C

Current opinion in structural biology 20160617

Therapeutic proteins are powerful next-generation drugs able to effectively treat diverse and devastating diseases, but the development and use of biotherapeutics entails unique challenges and risks. In particular, protein drugs are subject to immune surveillance in the human body, and ensuing antidrug immune responses can cause a wide range of problems including altered pharmacokinetics, loss of efficacy, and even life-threating complications. Here we review recent progress in technologies for ...[more]

PMID: 27322891

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Project description:Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies (TE-ADA) and presence of pre-existing ADA in drug-naïve individuals as risk-profiling strategies. Pre-existing ADAs are routinely identified during clinical immunogenicity assessment, but their origin and impact on drug safety and efficacy have not been fully elucidated. One specific class of pre-existing ADAs has been described, which targets neoepitopes of antibody fragments, including Fabs, VH, or VHH domains in isolation from their IgG context. With the increasing number of antibody fragments and other small binding scaffolds entering the clinic, a widely applicable method to mitigate pre-existing reactivity against these molecules is desirable. Here is described a structure-based engineering approach to abrogate pre-existing ADA reactivity to the C-terminal neoepitope of VH(H)s. On the basis of 3D structures, small modifications applicable to any VH(H) are devised that would not impact developability or antigen binding. In-silico B cell epitope mapping algorithms were used to rank the modified VHH variants by antigenicity; however, the limited discriminating capacity of the computational methods prompted an experimental evaluation of the engineered molecules. The results identified numerous modifications capable of reducing pre-existing ADA binding. The most efficient consisted of the addition of two proline residues at the VHH C-terminus, which led to no detectable pre-existing ADA reactivity while maintaining favorable developability characteristics. The method described, and the modifications identified thereby, may provide a broadly applicable solution to mitigate immunogenicity risk of antibody-fragments in the clinic and increase safety and efficacy of this promising new class of biotherapeutics.

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Design and engineering of deimmunized biotherapeutics.

Publications

Design and engineering of deimmunized biotherapeutics.

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