Building blocks for bispecific and trispecific antibodies

Wu, Xiufeng; Demarest, Stephen J.

doi:10.1016/j.ymeth.2018.08.010

Cited by 29 publications

(17 citation statements)

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“…This demonstrates that the additional binding capacity does not come at the cost of decreased overall antibody functionality compared to the original antibody. A wide range of multispecific antibody formats have been described in the literature, which may each have their unique strengths when targeting different neurodegeneration-related targets [83]. Bispecific antibodies are therefore a promising approach and could be explored against a wide range of target combinations to obtain potential synergistic effects.…”

Section: Resultsmentioning

confidence: 99%

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Quint¹,

Matečko-Burmann

Schilcher

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Quint¹,

Matečko-Burmann

Schilcher

et al. 2020

Preprint

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“…Effective TsAbs have been developed in infectious diseases [78] and cancer [79,80]. There are many formats for building TsAbs, from scFvs and VHH to Fab fusions [81]. Wu et al have described orthoTsAbs binding PD-1, CD137, and CTLA4 molecules based on Fab fusions [79].…”

Section: Antibodies For Tolerant Dendritic Cellsmentioning

confidence: 99%

Tethering Innate Surface Receptors on Dendritic Cells: A New Avenue for Immune Tolerance Induction?

Lamendour

Deluce-Kakwata-Nkor

Mouline

et al. 2020

IJMS

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Dendritic cells (DCs) play a key role in immunity and are highly potent at presenting antigens and orienting the immune response. Depending on the environmental signals, DCs could turn the immune response toward immunity or immune tolerance. Several subsets of DCs have been described, with each expressing various surface receptors and all participating in DC-associated immune functions according to their specific skills. DC subsets could also contribute to the vicious circle of inflammation in immune diseases and establishment of immune tolerance in cancer. They appear to be appropriate targets in the control of inflammatory diseases or regulation of autoimmune responses. For all these reasons, in situ DC targeting with therapeutic antibodies seems to be a suitable way of modulating the entire immune system. At present, the field of antibody-based therapies has mainly been developed in oncology, but it is undergoing remarkable expansion thanks to a wide variety of antibody formats and their related functions. Moreover, current knowledge of DC biology may open new avenues for targeting and modulating the different DC subsets. Based on an update of pathogen recognition receptor expression profiles in human DC subsets, this review evaluates the possibility of inducing tolerant DCs using antibody-based therapeutic agents.

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“…These therapies include promising new modalities, such as bispecific (e.g. blocking both TNF‐α and IL‐17) , and even trispecific antibodies , as well as vaccines . A compilation of these new and emerging treatment options for psoriasis can be found in Table 2.…”

Section: From Disease Understanding To Biomarkers Endotypes and Tarmentioning

confidence: 99%