Catalyzing a change in how we treat Alzheimer’s

Covalent Bioscience’s Stephanie Planque explains why longevity therapies should be converting to catalytic antibodies.

Covalent Bioscience was formed by Richard Massey, Sudhir Paul and Stephanie Planque to leverage catalytic antibody tech for unmet medical needs. Catalytic antibodies (sometimes called abzymes or catmabs, but preferably catabodies) are, as you might guess, antibodies that have catalytic abilities, and Paul and Planque made scientific headlines when they engineered a catalytic antibody that could render the HIV virus inert [1].

Covalent Bioscience is developing two catabodies to treat amyloid diseases of the heart, musculoskeletal system and brain, and one catabody for treating tauopathy of the brain. They also hope to expand the medical reach of its platform to on-demand production of catabodies for any pre-specified target protein, generating novel lead products for unmet needs across multiple areas of medicine.

Longevity.Technology: Covalent Bio’s cofounders share the conviction that the biotech’s platform holds the potential to generate superior immunotherapeutic drugs and vaccines. Paul describes catalytic antibodies as having exquisite specificity [2], and using them for novel therapies is an intriguing proposition. Ariel Feinerman, the Founder and Chief Science Officer of IntraClear Biologics, sat down with Principal Scientist Dr Stephanie Planque to find out more about this interesting technology and the platform that leverages it.

From its start in 2010, Covalent Bioscience has grown to a preclinical stage company holding significant assets.

“We have three promising lead products for diseases that proved very difficult to treat and prevent by conventional means,” explains Planque. “Two of them are catabodies for treating age-associated diseases such as Alzheimer’s disease and transthyretin amyloidosis. The products are expected to remove toxic aggregates that cause diseases in a more efficient and safe manner than conventional antibodies.”

A therapeutic toolbox

Covalent Bioscience’s main focus is, first, to optimize its on-demand toolbox; this toolbox enables generation of therapeutic catabodies and diagnostic irreversible antibodies with selectivity for virtually any protein target. The company’s second focus is on accomplishing preclinical milestones related to its lead antiaging catabodies, Alzyme and Tauzyme for clearing brain amyloid and tau proteins in Alzheimer’s disease, and Cardizyme for clearing heart and spinal cord amyloid caused by transthyretin, a transport protein in the plasma and CSF that transports the thyroid hormone thyroxine and retinol to the liver.

The technology in play is based on using special chemically modified analogs of the target to isolate or generate catabodies; these are able to permanently modify the target via enzymatic reaction or irreversible antibodies (IrAbs), which bind permanently to the target.

Catalyzing a change in how we treat Alzheimer's
Dr Stephanie Planque is Principal Scientist at Covalent Bioscience

“These chemically modified target analogs can be used as probes to isolate catabodies or IrAbs from antibody libraries or as electrophilic vaccines (E-Vaccines) to induce a polyclonal catabodies and IrAb response,” Planque explains.

Bait and switch

Planque says the chemical modification consists in attaching electrophilic moieties, or parts of molecules, on the surface of the target; this fulfills two important goals.

“First, we want target-specific catabodies or IrAbs,” she explains. “The polypeptidic component of the target binds non-covalently to target-specific antibody displayed on surface of phage or B cells (B cell receptor, or BCRs).”

In addition, says Planque, the electrophilic moiety is a bait and is designed to mimic the natural weak electrophilic carbonyl present in the target. It forms a non hydrolyzable (or covalent) bond with the active site, trapping the immune complex and preventing the hydrolysis step.

Planque explains that when switching to the native target, the selected or induced catabodies will be capable of attacking the natural weakly electrophilic carbonyls that are naturally present in these native targets and they will be able to hydrolyze the target.

Conventional antibodies are used as therapeutic and diagnostic agents, with their mechanism of action reliant on binding specifically to a target. One antibody molecule binds to one target molecule, but catabodies have the ability to modify and destroy multiple target molecules, which means, Planque explains, they are a therapeutic agent that is more efficient at removing toxic targets.

“Conventional antibodies have the intrinsic limitation of dissociating from the target, the binding is reversible,” she adds. “In contrast, IrAbs binds any target covalently and therefore is a diagnostic agent that is more efficient at detecting targets.”

Covalent’s first-in-class lead catabody products for age-associated major unmet needs – Alzyme and Cardizyme – clear amyloid plaques. Alzheimer’s drugs that clear amyloid β plaques from the brain have made headlines, but are not without side effects, including edema, microbleeds and death. Planque says that Alzyme stands up as an alternative.

“In mice, Alzyme removed Aβ amyloid without causing inflammation,” she explains. “Aβ-binding antibodies are fundamentally flawed drugs for Alzheimer’s because they rely on a brain-damaging inflammatory mechanism to remove amyloid. In contrast, catabodies remove disease-causing amyloids without inflammation.” 

She further explains, why catabodies are better solutions than conventional antibodies:

“Covalent’s lead anti-amyloid catabodies are the best solution because they permanently and directly destroy thousands of targeted amyloid copies (Aβ, tau or TTR) without inflammation or blood vessel damage. In contrast, competing drug candidates: (a) work reversibly on a 1:1 basis, (b) require inflammatory cell participation for amyloid removal, (c ) can cause inflammation and vascular damage that nullify the amyloid removal benefit, or (d) can interfere with normal bodily processes requiring the properly folded, non-amyloid version of the protein target.”

The Amyloid Hypothesis is not the whole story, of course; accumulation of lipofuscin and tau tangles have both been implicated in the progression of Alzheimer’s. Covalent is developing a prototype catabody to misfolded tau to be used in combination with Alzyme.

“Our technology can induce catabodies or IrAb to any targets,” explains Planque. “Hence, in addition to developing catabodies for any extracellular or intracellular amyloids, catabodies could be generated to dissolve lipofuscin accumulating during aging or to destroy any protein regulating cell loss, tissue atrophy, inflammation or cancerous cells could further help in fighting aging.”

Electrophilic education

As well as the catabody research, Covalent Biosciences is also developing electrophilic vaccines, or E-Vaccines, for short. With a target modified to present an electrophilic moiety on its surface, the goal of the E-vaccine is to teach the body to make catabodies or IrAbs and therefore protect the vaccinated individual when exposed to toxic substances or microbes.

“Vaccines are shown to stimulate the body’s own immune system to produce protective catabodies and IrAbs to protein targets involved in infectious disease and accelerated aging,” explains Planque. “As the catabodies and IrAbs show protective activity superior to the ordinary vaccine-induced rAbs, E-vaccines are predicted to show superior efficacy in disease prevention. Further, the E-vaccine targeting range is also superior to ordinary vaccines – they can target the functionally important regions of the protein target hidden to ordinary vaccines.”

Planque says that E-vaccine tech holds special promise for effective prevention of infections caused by mutable microbes (such as HIV, and SARS-coronavirus-2 ) and that the technology can also be adapted to develop longevity vaccines

Next steps

Covalent Bioscience plans to bring Alzyme to market either alone or in combination with Tauzyme, as a therapy for clearing brain amyloid protein in Alzheimer’s. The company also plans to move forward with Cardizyme as a treatment for clearing heart and spinal cord amyloid caused by the transthyretin protein.

Planque confirmed the company is completing some preclinical efficacy studies for Alzyme in animals, forecasting human trials in 2-3 years’ time. A similar timeline is expected for Cardizyme, whereas Tauzyme requires additional preclinical testing and is slated to reach human trials within 4 years. Actively seeking investment, Covalent is looking for funding to underwrite the milestones of manufacturing, animal toxicity profiles and Phase 1 human trials of the catabodies. Planque says the company hopes to raise $4.6 million to complete final Alzyme preclinical milestones and Phase 1 trials in Alzheimer patients, $4.7 million to complete molecular and animal optimization of Tauzyme and advance the Tauzyme catabody in combination with Alzyme in Alzheimer’s patients, and about $6 million to test Cardizyme in patients with heart disease or lumbar spinal stenosis.

[1] https://pubmed.ncbi.nlm.nih.gov/20822346/
[2] https://link.springer.com/content/pdf/10.1007/BF02821514.pdf