Biochemical Properties of Lomecel-B
The proposed mechanisms of action of Lomecel-B derive from intrinsic cellular features. Lomecel-B cells secrete numerous proteins that include cytokines and growth factors, which are believed to be responsible for decreasing inflammation and promoting repair.
Lomecel-B also secretes exosomes, which are biochemically active membrane spheres (called vesicles) that carry cargo composed of proteins, ribonucleic acid (RNA), and other molecules. MSC exosomes have been found to include over a thousand proteins and hundreds of different RNAs that can have beneficial effects on numerous pathways. Using exosomes as a therapeutic is an emerging therapeutic principle that we are pursuing through our research and development.
Lomecel-B cells can also potentially regulate endogenous cells through actions that include direct cell-cell interactions that can allow for exchange of RNAs, proteins, and other cellular content between the cells through linkages called connexin-mediated gap-junctions. MSCs can also form TNTs that allow for exchange of larger cytoplasmic content, including mitochondria (the energy-generating portions of cells). Such exchanges have been documented to occur between MSCs and neuronal stem cells, cardiomyocytes, corneal epithelial cells, lung epithelial cells, retinal ganglion cells, renal epithelial cells, and macrophages.
In the context of treating aging-related disorders, such exchange of mitochondria, proteins, RNA, and other cargo from Lomecel-B sourced from young donors may suggest cellular regenerative mechanisms for older cells of the recipient which have depleted mitochondria, reduced metabolic functioning, etc. In fact, mitochondria released from damaged cells appears to be a signal to induce regenerative mechanisms in MSCs, which can promote a desired shift in energy metabolism in the recipient cells.
Pleiotropic Mechanisms of Action
Potential Mechanisms of Action of Lomecel-B
(1) Lomecel-B cells release growth factors and other proteins, such as anti-inflammatory cytokines. These have the potential to reduce inflammation, and stimulate nearby stem cells and other cells (called paracrine activity) to promote regenerative and repair responses. There is also potential for these factors to be released into the blood and work at a distance, called endocrine activity. (2) Lomecel-B cells also have the potential to engage in direct cell-cell interactions to induce positive pathways in contacted cells. (3) Lomecel-B cells release exosomes, which have cargo consisting of RNA, proteins, and other molecules that can be taken up by other cells to provide beneficial effects. (4) Lomecel-B cells also have the potential to form nanotube bridges, which can allow the exchange of mitochondria and other cellular contents between cells.
Key Features and Potential Benefits of Lomecel-B
The key features of Lomecel-B offer potential benefits as a possible geroscience therapeutic, including the following:
● “Off-the-Shelf” and scalable product. Lomecel-B is intended to be an “off-the-shelf” commercialized product that is stored frozen and available for on-demand use. To date, it has been safely administered without eliciting a rejection or allergic response from the recipient. This is because MSCs have unique properties that inhibit a graft rejection response. This property is also known as being immunoprivileged/immunoevasive, and thus Lomecel-B does not require tissue-type matching. Each lot of Lomecel-B is derived from a young, healthy, highly-screened donor, where the cells are present in relatively small quantities. Lomecel-B cells are then culture-expanded in vitro to produce orders of magnitude more cells, which are then cryopreserved and stored for future use. These are advantages over autologous cell therapy interventions, which involve removing cells from an individual through an operative procedure, and then reintroducing the cells back into the same person, sometimes after weeks of culture expansion. Accordingly, autologous approaches lack economies of scale since they serve only a single patient. In our clinical trials, Lomecel-B is administered through intravenous infusion in under one hour on an outpatient basis, or via direct tissue injection, depending upon the indication.
● Enduring effects. Our clinical data suggests that the effects of a single dose of Lomecel-B may last over 6 months. This is consistent with previous studies showing human MSCs can persist for months in immunocompetent hosts, thereby helping support the potential duration of effect.
● Young phenotype. The starting raw material source for Lomecel-B is young healthy adult donors. Such sourced cells can provide significantly higher potency over similarly prepared autologous MSCs (i.e., sourced from a person they will be given back to). In the context of aging-related conditions, autologous MSCs can be impaired by advanced age and/or patient co-morbidity. Relative to young adults, MSCs from older adults have reduced regenerative potential, as indicated by: diminished proliferative capacity; diminished differentiation potential; increased senescence; increased expression of deoxyribonucleic acid (DNA)-break repair genes; altered DNA-methylation and gene-expression patterns; impaired migration; altered expression of microRNAs and cell-surface markers; and diminished anti-inflammatory activity. The sourcing and manufacturing of Lomecel-B are designed to minimize these confounding issues.
● Safe and consistent manufacturing. Lomecel-B manufacturing is performed in our facility using cGMP-compliant processes. The donors used for sourcing Lomecel-B undergo rigorous screening to ensure safety, including screening for communicable diseases and illicit drug use that exceed federal guidelines. Throughout the production process, the cells are analyzed according to pre-established criteria to ensure that a consistent, well-characterized, safe product candidate is produced.
● Demonstrated consistent safety. Lomecel-B has thus far in our clinical trials shown a high safety profile. Over 250 subjects have been administered Lomecel-B, and no SAEs have been reported that were considered related to the product candidate. This is consistent with published reports for allogeneic MSCs, which show a high safety profile, high tolerability, and no malignant transformation.
● Support for efficacy from early clinical trial data. As described above and supported by our clinical results, Lomecel-B has multiple potential MOAs that can potentially address broad aging-related disorders. This has potential advantages over small molecule drugs and biologics that have highly-specific targeting.
● Potency, identity, and efficacy assays. We are developing these assays for Lomecel-B as part of our early stage trials, for validation in our pivotal Phase 3 trials. These assays are important steps required by FDA prior to product approval and are needed to qualitatively identify and quantitatively measure biological activity of the product candidate.
Aging and Immunosenescence
A lifetime of exposure to repeated infection, stress, antigens (allergens, food, chemicals) leaves the human body in a state of chronic inflammation and immunosenescence. The immune system remodels. Innate immune response weakens. Stem cells, responsible for repair and regeneration, decrease logarithmically. Multisystem decline in function advances. Immunosenescence leads to increased susceptibility to infection with COVID-19 and influenza. We become frail. We cannot fight off infection. We are vulnerable. The aging process itself is the major risk factor for aging-related disorders. Pathological mechanism involved in aging-related disorders include: chronic inflammation, diminished stem cell function, cellular senescence, and loss of endogenous repair mechanisms.
Human Mesenchymal Stem Cells (MSCs) Decline with Age
•By 2050, approximately 21.3% of the global population will be 60 years or older
•Overall prevalence of frailty is 7-12%, or 4.76 million to 8.16 million US citizens.
•Frailty phenotype includes weight loss, sarcopenia, fatigue and slowness
Frail people experience a decrease in homeostasis, diminished functionality, and inability to respond to a stressor (e.g. surgery, infection, fall) leading to dependence and disability.
Inability to mount appropriate immune response kills disproportionate amount of frail people. Major risk factor for influenza, COVID-19 and resulting pneumonia and ARDS. Our survival depends on the ability of our immune system to respond to potentially deadly pathogens. Impaired immune responses in aging and frailty reduces quality of life and increases susceptibility to infectious diseases. Age related chronic inflammation (inflammaging) leads to deficits in both the T and B cells numbers and function. Albeit immunosuppressive qualities of MSCs, their anti-inflammatory quality may reverse the effects of aging and frailty improving the already suppressed immune system.