A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

Abstract

Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro , PMN310 inhibited AßO propagation and toxicity. In vivo , PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

“…The next generation of anti-oligomer therapeutics with improved selectivity and product profiles includes the following agents and mechanisms: (1) PMN310, an anti-amyloid antibody that selectively clears formed Aβ oligomers; (2) CT1812, a small molecule that inhibits Aβ oligomer binding to specific neuronal receptors that mediate neurotoxicity; and (3) PQ912 and ALZ-801, small molecules that prevent the formation of neurotoxic soluble Aβ oligomers. An example of an antibody designed to be highly selective to Aβ oligomers is PMN310 from ProMIS Neuroscience [ 49 ], which is in preclinical development. CT1812 is an oral small molecule from Cognition Therapeutics that inhibits the binding of Aβ oligomers to sigma-2 receptors [ 50 ], which is thought to mediate some of the oligomer-induced synaptic toxicity.…”

Passive immunotherapies targeting Aβ and tau in Alzheimer's disease

“…PMN310 is a humanized IgG4 antibody that binds a conformational epitope consisting of 13 HHQK 16 , specifically when presented on low-molecular weight oligomers and protofibrils. The antibody shows no apparent binding to A β monomer, amyloid plaque, or vascular deposits ( Gibbs et al (2019) ). This is a potential advantage to avoid target distraction by more abundant monomers, and if clearing plaque does not correlate with cognitive benefit.…”

“…Immunohistochemical studies show that PMN310 exhibits essentially no binding to A β plaque in AD brain samples, supporting greater selectivity of PMN310 to A β oligomers and reduced risk of ARIA-related adverse effects compared to other antibodies currently in clinical development such as aducanumab and BAN2401. The murine precursor muPMN310 inhibited A β 42 aggregation in ThT assays, and increased viability of neurons in in vitro MTT metabolic assays ( Gibbs et al (2019) ). PMN310 was also observed to block the effects of toxic oligomers on short-term memory loss in mice, as assessd by the novel object recognition test ( Kaplan et al (2019) ; Gibbs et al (2019) ).…”

“…The murine precursor muPMN310 inhibited A β 42 aggregation in ThT assays, and increased viability of neurons in in vitro MTT metabolic assays ( Gibbs et al (2019) ). PMN310 was also observed to block the effects of toxic oligomers on short-term memory loss in mice, as assessd by the novel object recognition test ( Kaplan et al (2019) ; Gibbs et al (2019) ).…”

Faculty Opinions recommendation of The beta amyloid dysfunction (BAD) hypothesis for alzheimer's disease.

“…Such antibodies have been described, e.g., 4D10 and similar globulomerderived antibodies (Hillen et al, 2010;Barghorn et al, 2011Barghorn et al, , 2012. Other groups describe the generation of Aβ oligomer selective antibodies obtained by immunization with loop peptides (Gibbs et al, 2019).…”