What is ageing? We can define ageing as a process of accumulation of the damage which is just a side-effect of normal metabolism. While researchers still poorly understand how metabolic processes cause damage accumulation, and how accumulated damage causes pathology, the damage itself – the structural difference between old tissue and young tissue – is categorized and understood pretty well. By repairing damage and restoring the previous undamaged – young – state of an organism, we can really rejuvenate it! It sounds very promising, and so it is. And for some types of damage (for example, for senescent cells) it is already proved to work! Today in our virtual studio, somewhere between cold, rainy Saint-Petersburg and warm, sunny Huston, we meet Stephanie Planque! For those of you who are not familiar with her, here is a brief introduction. Stephanie Planque was awarded the PhD in 2009 by the University of Texas-Houston Medical School for her advances in applying electrophilic analogs of proteins to decipher the beneficial and harmful functional effects of catabodies. She then expanded her focus to vaccination and therapeutic catabody identification using proprietary electrophilic target analogs. Her work was published in 49 peer-reviewed scientific articles, she has numerous national/international conference presentations. She moved fulltime as a co-founder to Covalent Bioscience in 2018 to focus on rapidly translating their electrophilic vaccine/catabody technologies to clinical reality. Note: If you have not read “Ending Aging” yet I suggest you to do it as soon as possible, and to be more comfortable with the ideas we are discussing below I highly recommend you to read short introduction to SENS research on their web page. Also if you are interested in recent news and up to date reviews about [anti]ageing and rejuvenation research the best place to look for is Fight Aging! blog. Finally, if you are an investor or just curious, I highly encourage you to take a look at Jim Mellon’s book “Juvenescence”. Ariel Feinerman: Hello, Dr Stephanie Planque! Stephanie Planque: Hi, Mr Feinerman! Happy to participate in this interview. Ariel Feinerman: What is the brief history of Covalent Bioscience? Stephanie Planque: Covalent Bioscience was incorporated in 2010 by Dr Sudhir Paul and Dr Richard Massey based on catalytic antibody technology and several exciting potential products for unmet medical needs. The technology and potential products were developed in Dr Sudhir Paul’s group at the University of Texas (UT). Dr Richard Massey and Dr Sudhir Paul have worked together on the field of catalytic antibody (or catabody) when Dr Massey was in Igen in the late 80’s. I have worked with Dr Paul since 1999 and am one of the co-founders of Covalent Bioscience. We, the founders of Covalent Bioscience, share the same conviction that our platform technology holds the potential to generate superior immunotherapeutic drug and vaccines. Today, Covalent Bioscience has grown to a preclinical stage company holding significant assets. Our broad technology platform can be applied to generate novel lead products for unmet needs across multiple areas of medicine. We have three promising lead products for diseases that proved very difficult to treat and prevent by conventional means. 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. In 2018, Dr Paul and I moved full time to Covalent Bioscience. Our lab is located at the skirt of the Houston Medical Center, biggest Medical Center in the World. In 2020, Covalent Bioscience received from The University of Texas the commercial rights to all inventions and research materials/tools Paul’s team generated there. With our current funding, we are generating new catabodies and working in collaboration with a Pharma to advance one of our lead products closer to human trials. Ariel Feinerman: What is the main focus of your research? Stephanie Planque: Our main focus is, first, to optimize our an on-demand toolbox that enables generation of therapeutic catabodies and diagnostic irreversible antibodies with selectivity for virtually any protein target. Second, we want to accomplish preclinical milestones related to our anti-aging lead catabodies, Alzyme and Tauzyme for clearing brain amyloid proteins in Alzheimer’s disease, and Cardizyme for clearing heart and spinal cord amyloid caused by the transthyretin protein. Ariel Feinerman: What is the basis of your technology? Stephanie Planque: Our technology is based on using special chemically modified analogs of the target to isolate or generate catabodies, which modify permanently the target via enzymatic reaction or irreversible antibodies (IrAbs), which bind permanently to the target. 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. The chemical modification consists in attaching electrophilic moieties on the surface of the target to fulfill two important goals. First, we want target-specific catabodies or IrAbs. 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). Second, the electrophilic moiety is a bait and is designed to mimic the natural weak electrophilic carbonyl present in the target and to form a non hydrolyzable (or covalent) bond with the nucleophilic active site (negatively charged) of a catabody or IrAbs expressed on the B cell surface as BCRs or expressed on phage display. This covalent bond traps the immune complex and prevents the hydrolysis step. However, when switching to the native target, the selected or induced catabodies will be capable to attack the natural weakly electrophilic carbonyl naturally present in the native target and hydrolyze the target. Ariel Feinerman: Can you tell more how catabodies work? What are their unique properties? Which ageing pathology can you treat with them? Stephanie Planque: The conventional antibodies are used as therapeutic and diagnostic agents. Their mechanism of action relies on binding specifically to target. One molecule of antibody binds one target molecule. In contrast, one catabody can modify and destroy multiple target molecules and therefore is 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. In contrast, IrAbs bind any target covalently and therefore is a diagnostic agent that is more efficient at detecting target. Covalent has developed two first-in-class lead catabody products for age-associated major unmet needs: Alzyme, for clearing amyloid β plaques from the brain for treating Alzheimer’s disease, and Cardizyme, for clearing transthyretin amyloid plaques from the spinal cord and heart for treating systemic amyloid disease. Two conventional antibodies to Aβ have been approved by FDA for Alzheimer’s disease to remove Aβ and improved cognition. They both are accompanied with inflammation in the brain caused by antibody~Aβ immune complex activated microglia that can cause major adverse effect (edema, microbleeds and death). In mice, Alzyme removed Aβ amyloid without causing inflammation. Aβ-binding antibodies are fundamentally flawed drugs for Alzheimer’s because they rely on brain-damaging inflammatory mechanism to remove amyloid. In contrast, catabodies remove disease-causing amyloids without inflammation. Ariel Feinerman: We know that Abeta is not the full story. There is Tau, chronic inflammation, lipofuscin. Stephanie Planque: To be used in combination with Alzyme, we are developing a prototype catabody to misfolded Tau, another misfolded protein that play a role in Alzheimer’disease but also other taupathy. Our technology can induce catabodies or IrAb to any targets. Hence, in addition to developing catabody to 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 ageing. Ariel Feinerman: What is E-Vaccine? How do they work? How do they differ from original vaccine? Stephanie Planque: We use the term “electrophilic vaccine” or “E-Vaccine” because the vaccine is composed of the target modified to present an electrophilic moiety on its surface. The goal of E-vaccine is to teach our body to make catabodies or IrAbs and that will protect the vaccinated individual when exposed to the toxic substance or microbes. E-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. 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. The E-vaccine technology holds special promise for effective prevention of infections caused by mutable microbes (such as HIV infection, the SARS-coronavirus-2 infectionf). The technology can also be adapted to develop longevity vaccines. This is supported by induction of catabodies and IrAbs in mice with a prototype electrophilic amyloid β peptides for protecting against Alzheimer. Covalent Bioscience also considers electrophilic misfolded transthyretin analogs to protect against transthyretin amyloidosis. The principle and benefits of E-vaccine come from our lead product, HIV E-Vaccine. Our HIV E-vaccine is composed of HIV coat protein gp120 with electrophilic moiety on Lys side chain. It was shown to induce catabodies and IrAbs that neutralize genetically diverse HIV strains in mice, rabbits and non-human primates. It also induces efficient IgMà IgG switch, of B cell with specificity for a conserved but poorly immunogenic epitopes of gp120. Covalent Bioscience intends to bring the vaccine to human trials stage. Ariel Feinerman: What products are you hoping to bring to market? What is your commercialization route? Stephanie Planque: We plan to bring to market our Alzyme for clearing brain amyloid protein in Alzheimer’s disease alone or in combination with Tauzyme. We also plan to move forward Cardizyme for clearing heart and spinal cord amyloid caused by the transthyretin protein. 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. We seek investment, partnership and licensing arrangements to develop our products and validate the commercial value of our technologies. Ariel Feinerman: When can we see your therapies in human clinical trials? Stephanie Planque: We are completing some preclinical efficacy studies for Alzyme in animals. Considering the need for GMP-grade production of Alzyme and submission of an IND to FDA, human trials for Alzyme would be within 2–3 years. Similar timeline is expected for Cardizyme. Tauzyme requires additional preclinical testing and would reach human trials within 4 years. We are actively seeking funding and partner that would allow us to more rapidly have these three products to reach human trials. Ariel Feinerman: How are you funded? Stephanie Planque: The technology was developed at the University of Nebraska and University of Texas using funds received from NIH and other non-profit organization (The Richard J. Massey Foundation for Arts and Sciences, Abzyme Research Foundation, SENS Research foundation), investment from Founders and Angel investors. Angel investors constitute our current funding source. Covalent invites USD 4.5 million investment in exchange for equity to advance commercialization of these inter-related parts of its business plan over 18 months for developing our on-demand toolbox and our anti-aging lead catabodies. Ariel Feinerman: How much money do you need to bring your therapies to the clinic? Stephanie Planque: The funding will underwrite the milestones of manufacturing, animal toxicity profiles and Phase 1 human trials of the catabodies. Covalent will need about $4.6M to complete final Alzyme preclinical milestones and Phase 1 trials in Alzheimer patients; about $4.7M to complete molecular and animal optimization of Tauzyme and advance the Tauzyme catabody in combination with Alzyme in Alzheimer patients; about $6M to test Cardizyme in patients with heart disease or lumbar spinal stenosis. Ariel Feinerman: Thank you very much for your interview! Stephanie Planque: Thank you for your interest in Covalent Bioscience.  Исследователь, автор и переводчик