Catalytic Antibodies Targeting Transthyretin Amyloid (University of Texas)
As part of the degenerative aging process, proteins that normally remain dissolved in bodily fluids become damaged, and adopt a misfolded form called amyloid. One form of amyloid that is composed of the transporter protein transthyretin (TTR) deposits in the heart and other organs with age, beginning to impair heart function in 20-25% of individuals over the age of 80, with increasing prevalence and severity at later ages. No other organization is funding research targeting aggregates composed of wild-type TTR. This makes wild-type TTR a critical-path target for the Foundation.
In loose collaboration with Foundation-funded research on diagnostic and potentially sequestering antibodies at Brigham & Women’s Hospital (see the corresponding Extramural Research section on the website), the UTHMS extracellular aggregate team is working to develop novel catalytic antibodies (“catabodies”) that would recognize and cleave TTR amyloid deposits deposited in the heart and other tissues. They have developed a system to identify native catabodies and engineered catabody fragments with more powerful amyloid-cleaving capacity, which can be used to augment the body’s natural catabody defense system and prevent or reverse diseases of aging driven by extracellular aggregates.
With Foundation funding, the UTHSC group have been able to identify native TTR aggregate-targeting catabodies and catabody fragments present in serum samples from young volunteers that were sufficient to account for nearly all of this cleaving activity. The effect was specific to misfolded TTR, leaving TTR in its native conformation untouched. To mass-produce these native catabodies, the UTHMS team identified subsets of antibody-producing B-cells from patient blood that selectively recognized aggre- gated TTR, and then applied gene therapy to those B-cells in culture to allow them to proliferate indefinitely and continue generating the needed antibodies. The team’s three lead catabody candidates appear to be highly selective amyloid-mincers that leave normal proteins alone, target aggregated TTR, powerfully hydrolyze its molecular bonds, quickly release amyloid fragments, and turn immediately to the next molecule of aggregate for destruction. An important next step will be to develop better ways to purify the candidate catabodies from the B-cell culture fluid. They are now working on a new method using gel filtration combined with ion-exchange chromatography, which should allow for catabodies to be purified while fully preserving hydrolytic activity. The researchers are also investigating whether they can sustain the catabodies’ activity (potentially yielding a more effective rejuvenation therapy) if they are separated into a monomer form.
With continued progress, the team is looking to perform more robust proof-of-concept tests in two lines of mice engineered to express wild-type human TTR and common disease-associated mutations, using infused catabodies and possibly transfer of genes into cells in affected tissue for local secretion. Catabodies against beta-amyloid generated separately have already reached this stage and are performing very well.