scholarly journals Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein

2021 ◽  
Vol 80 (2) ◽  
pp. 813-829
Author(s):  
Wim Hendricus Quint ◽  
Irena Matečko-Burmann ◽  
Irene Schilcher ◽  
Tina Löffler ◽  
Michael Schöll ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Alpha Synuclein ◽  
Initiation Factor ◽  
Bispecific Antibodies ◽  
Complement Pathway ◽  
Tau Pathology ◽  
Classical Complement Pathway ◽  
Classical Complement

Background: Alzheimer’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. Objective: 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. Methods: Herein, 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. Results: 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. Conclusion: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

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

2020 ◽  
Author(s):  
Wim Hendricus Quint ◽  
Irena Matečko-Burmann ◽  
Irene Schilcher ◽  
Tina Löffler ◽  
Michael Schöll ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Alpha Synuclein ◽  
Initiation Factor ◽  
Bispecific Antibodies ◽  
Complement Pathway ◽  
Tau Pathology ◽  
Classical Complement Pathway ◽  
Classical Complement

AbstractBackgroundAlzheimer’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.

scholarly journals Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Emil Gregersen ◽  
Cristine Betzer ◽  
Woojin S. Kim ◽  
Gergo Kovacs ◽  
Lasse Reimer ◽  
...  
Keyword(s):  
Complement System ◽  
Cell Model ◽  
Alpha Synuclein ◽  
Postmortem Brain ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Activation Assay ◽  
The Complement System ◽  
Classical Complement

Abstract Background Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer’s disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology. Methods To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients. Results We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls. Conclusion α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.

scholarly journals Carbamylation of immunoglobulin abrogates activation of the classical complement pathway

2014 ◽  
Vol 44 (11) ◽  
pp. 3403-3412 ◽  
Author(s):  
Catalin Koro ◽  
Ewa Bielecka ◽  
Anders Dahl‐Knudsen ◽  
Jan J. Enghild ◽  
Carsten Scavenius ◽  
...  
Keyword(s):  
Complement Pathway ◽  
Classical Complement Pathway ◽  
Classical Complement

scholarly journals Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

2006 ◽  
Vol 80 (8) ◽  
pp. 4038-4046 ◽  
Author(s):  
Lauren M. Hook ◽  
John M. Lubinski ◽  
Ming Jiang ◽  
Michael K. Pangburn ◽  
Harvey M. Friedman
Keyword(s):  
Herpes Simplex ◽  
Human Serum ◽  
Immunoglobulin M ◽  
Complement Pathway ◽  
Glycoprotein C ◽  
Classical Complement Pathway ◽  
Simplex Virus ◽  
Classical Complement ◽  
Hsv 1

ABSTRACT Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) binds complement component C3b and protects virus from complement-mediated neutralization. Differences in complement interacting domains exist between gC of HSV-1 (gC1) and HSV-2 (gC2), since the amino terminus of gC1 blocks complement C5 from binding to C3b, while gC2 fails to interfere with this activity. We previously reported that neutralization of HSV-1 gC-null virus by HSV antibody-negative human serum requires activation of C5 but not of downstream components of the classical complement pathway. In this report, we evaluated whether activation of C5 is sufficient to neutralize HSV-2 gC-null virus, or whether formation of the membrane attack complex by C6 to C9 is required for neutralization. We found that activation of the classical complement pathway up to C5 was sufficient to neutralize HSV-2 gC-null virus by HSV antibody-negative human serum. We evaluated the mechanisms by which complement activation occurred in seronegative human serum. Interestingly, natural immunoglobulin M antibodies bound to virus, which triggered activation of C1q and the classical complement pathway. HSV antibody-negative sera obtained from four individuals differed over an approximately 10-fold range in their potency for complement-mediated virus neutralization. These findings indicate that humans differ in the ability of their innate immune systems to neutralize HSV-1 or HSV-2 gC-null virus and that a critical function of gC1 and gC2 is to prevent C5 activation.

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