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.

08 Jan 2020·Science Translational MedicineQ1 · MEDICINE

A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies

Q1 · MEDICINE

Article

Author: Thurston, Gavin ; Golubov, Jacquelynn ; Canova, Lauren ; Ramos, Ilyssa ; Dudgeon, Drew ; Haber, Lauric ; Poon, Patrick ; Havel, Lauren ; Ye, Xuan ; Ullman, Erica ; Provoncha, Kathleen ; Yancopoulos, George D. ; Vazzana, Kristin ; Smith, Eric ; Herlihy, Evan ; Lin, John ; Siao, Chia-Jen ; Kim, Julie ; Stokes Oristian, Nicole ; Kirshner, Jessica R. ; Crawford, Alison ; Wang, Bei ; Oswald, Erin ; Poueymirou, William ; Warsaw, Jacqueline J. ; Ajithdoss, Dharani ; Hermann, Aynur ; Wu, Qi ; Sleeman, Matthew A. ; Skokos, Dimitris ; Rafique, Ashique ; Slim, Rabih ; Waite, Janelle C. ; Ahmed, Hassan ; Lazo, Miguel ; Yu, Kevin ; Godin, Stephen ; MacDonald, Douglas ; Ram, Priyanka ; Murphy, Andrew J. ; Potocky, Terra ; Olson, William ; Huang, Tammy ; Chiu, Danica ; Martin, Joel ; Oyejide, Adelekan ; Pawashe, Arpita

CD28 bispecific antibodies are well tolerated and enhance the antitumor efficacy of CD3 bispecifics as a potential off-the-shelf antibody therapy.

01 May 2011·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains

Q2 · MEDICINE

Article

Author: Dormeyer, Wilma ; Schäfer, Wolfgang ; Hoffmann, Eike ; Zhang, Jun ; Brinkmann, Ulrich ; Jekle, Andreas ; Cammack, Nick ; Umana, Pablo ; Stracke, Jan ; Heilek, Gabrielle ; Ji, Changhua ; Croasdale, Rebecca ; Dioszegi, Marianna ; Brandt, Michael ; Lochner, Adriane ; Schanzer, Jürgen ; Nezu, Junichi

ABSTRACT In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly 4 Ser) n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linkers, stable molecules could be obtained in amounts that were within the same range as or no less than 4-fold lower than those observed with monoclonal antibodies in transient expression assays. In contrast to monospecific CCR5 antibodies, bispecific antibody derivatives block two alternative docking sites of CCR5-tropic HIV strains on the CCR5 coreceptor. Consequently, these molecules showed 18- to 57-fold increased antiviral activities compared to the parent antibodies. Most importantly, one prototypic tetravalent CCR5 antibody had antiviral activity against virus strains resistant to the single parental antibodies. In summary, physical linkage of two CCR5 antibodies targeting different epitopes on the HIV coreceptor CCR5 resulted in tetravalent, bispecific antibodies with enhanced antiviral potency against wild-type and CCR5 antibody-resistant HIV-1 strains.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	F. Hoffmann-La Roche Ltd.	-
Neoplasms	Preclinical	-	Go Therapeutics, Inc.Startup	-

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