Potential Reversal of Alzheimer’s Disease pathology by Antibody TB006 Targeting Galectin‐3, the Root Cause of Oligomerization of Amyloid Proteins

Abstract Background Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder caused by multiple pathogenic factors including Amyloid‐β (Aβ), phospho‐Tau (pTau), alpha‐synuclein, and ApoE4, etc. It is widely accepted that intermediate oligomeric forms , rather than monomers or mature fibrils , are more neurotoxic. Galectin‐3 (Gal‐3) was reported to be involved in Aβ oligomerization. Here, we show that Gal‐3 promotes oligomerization of Aβ and other pathogenic factors, and TB006 , a monoclonal antibody targeting Gal‐3 , acts as a possible treatment for AD by degrading neurotoxic oligomers. Method We used two anti‐Gal‐3 antibodies, our clinical lead TB006 and a mouse cross‐reactive surrogate, mTB001, to establish the benefits of Gal‐3 neutralization in AD in vitro and in vivo. The effects of mTB001 were tested in three AD mouse models (two transgenic mouse models (APPSwe, 5xFAD) and an Aβ42‐injected mouse model). After two‐week treatment, a spatial memory function test was conducted, followed by biochemical and immunohistochemical characterizations. Result Amyloid aggregation is a hallmark of several neurodegenerative diseases (AD, PD and ALS) affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils) and final mature fibrils display different toxicity. In vitro, Gal‐3 intrinsically and selectively promotes, while mTB001 and TB006 degrade, oligomerization of only pathogenic proteins like Aβ42/40, α‐synuclein, pTau and ApoE4, but not of normal proteins like normal Tau and ApoE2/3. Gal‐3 enhanced, while mTB001 blocked, Aβ42‐induced microglia activation. Additionally, Aβ42 and Gal‐3 synergistically induced, while mTB001 reversed, neuronal death. In vivo, in three mouse models of AD, cognitive deficits were strongly attenuated after just two weeks of mTB001 treatment. Mechanistically, Gal‐3 antibody blocked the initiating events in AD (Aβ aggregates), reduced inflammation and rescued neuronal damage. Furthermore, microhemorrhages, a potential safety liability seen in clinical stage drugs, were reduced. Conclusion Pre‐clinical studies show that TB006 is an efficacious therapeutic entity through degradation of toxic oligomers and blocking or even reversing AD progression. Clinically, TB006 has shown a superior safety profile without any drug‐related adverse events in a nearly finished healthy volunteer trial. Promising efficacious data are expected in Q2/2022 from the ongoing phase I/II AD trial.