CLBS119

Our COVID-19 Response Efforts

Caladrius is leveraging our cell therapy expertise and resources to help patients and communities fighting the COVID-19 pandemic. We believe we are uniquely positioned to contribute to the combat of this public health threat using our proprietary CD34+ cell technology to help repair COVID-19 induced lung damage and restore human health.

CLBS119

CLBS119 is Caladrius’ CD34+ cell therapy product candidate targeting repair of COVID-19 induced lung damage. The FDA has authorized administration of CLBS119 under its Expanded Access IND Guidelines to evaluate the safety and efficacy of autologous, peripheral-blood-derived CD34+ cells for repair of COVID-19 induced lung damage in patients who have suffered respiratory failure.

Human Coronavirus Disease 2019

In December 2019, when a new pneumonia-like illness in China was identified as “Coronavirus Disease 2019” (COVID-19), Caladrius moved quickly to determine whether our CD34+ cell technology could play a role in responding to the growing public health threat. COVID-19 is caused by the virus “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). The extent of the disease, its epidemiology, pathophysiology and clinical manifestations are being well-documented on an ongoing basis (Guan et al. 2020; Yang et al. 2020).

Pulmonary injury is a principal cause of COVID-19 morbidity and mortality

One important feature of the COVID-19 infection is the predominance of pulmonary manifestations. To date, the reported fatalities have virtually all been accompanied by evidence of pneumonia and systemic inflammation (Zhou et al. 2020; Pan et al. 2020; Xu et al. 2020; Xie et al. 2020). In addition, anecdotal evidence indicates that attenuation of inflammation may be beneficial in COVID-19 pneumonia (Zhu et al. 2020).

Vascular endothelial damage appears to precipitate end-organ damage in COVID-19

Evidence is accumulating indicating that vascular endothelial injury may be a precipitating factor in severe organ damage caused by COVID (Varga et al. 2020). Varga et al found multiple examples of viral invasion of vascular endothelial cells associated with inflammation, endothelial cell death, microvascular dysfunction and organ failure. Tian et al identified evidence of vascular leakage in the lungs of COVID-19 patients (Tian et al. 2020) indicating a severe loss of vascular integrity. The authors also reported vascular congestion. In sum, the findings are consistent with inflammation and severe vascular damage.

Prior data from the SARS epidemic suggest that CD34+ cells in the lung could be a target of the COVID-19 infection and that destruction of lung CD34+ progenitors could account for the inability of patients with severe pulmonary manifestations to fully recover (Chen et al. 2007).

Evaluating our existing CD34+ Cell Technology for the Repair of COVID-19 Induced Lung Damage

CD34+ cells are well known as hematopoietic stem cells (Berenson et al. 1988). In 1997, Asahara et al. described another function of CD34+ cells as endothelial progenitor cells capable of inducing the formation of new vasculature (Asahara et al. 1997). This tissue repair capability was then documented in a variety of preclinical models (Taguchi et al. 2004; Kawamoto, Iwasaki, et al. 2006), leading to the clinical development of autologous CD34+ cell therapy in multiple indications. These clinical studies have yielded substantial evidence for safety and efficacy for reversal of tissue damage in humans (Kawamoto, Katayama, et al. 2006; Losordo et al. 2007; Kawamoto et al. 2009; Losordo et al. 2011; Losordo et al. 2012; Ohtake et al. 2018).

A component of the tissue repair capability of CD34+ cells is an anti-inflammatory function. The anti-inflammatory effects of human CD34+ cells have been documented in multiple pre-clinical models including models of severe lung inflammation (Huang et al. 2014; Lo et al. 2017; Abd-Allah et al. 2015). This evidence suggests that the severe pulmonary manifestations of COVID-19 that lead to long term disability and death are mediated by inflammation and vascular damage. CD34+ cells have pre-programmed tissue repair effects mediated by pro-angiogenic and anti-inflammatory functions.

Based on the evidence above, Caladrius is poised to launch the study of CLBS119 in a clinical trial to evaluate autologous CD34+ cell therapy for the repair of COVID-19 induced lung damage in patients who have suffered respiratory failure. The company is committed to responding to this public health threat with the highest urgency and plans to initiate the Phase 1/2 trial as soon as practical.

References:

Abd-Allah, S. H., et al. 2015. 'Human peripheral blood CD34+ cells attenuate oleic acid-induced acute lung injury in rats', Cytotherapy, 17: 443-53.
Asahara, T., et al. 1997. 'Isolation of putative progenitor endothelial cells for angiogenesis', Science, 275: 964-67.
Berenson, R. J., et al. 1988. 'Antigen CD34+ marrow cells engraft lethally irradiated baboons', J Clin Invest, 81: 951-5.
Chen, Y., et al. 2007. 'A novel subset of putative stem/progenitor CD34+Oct-4+ cells is the major target for SARS coronavirus in human lung', J Exp Med, 204: 2529-36.
Guan, W. J., et al. 2020. 'Clinical Characteristics of Coronavirus Disease 2019 in China', N Engl J Med.
Huang, X., et al. 2014. 'Human CD34+ progenitor cells freshly isolated from umbilical cord blood attenuate inflammatory lung injury following LPS challenge', PLoS One, 9: e88814.
Kawamoto, A., et al. 2006. 'CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells', Circulation, 114: 2163-9.
Kawamoto, A., et al. 2006. 'Safety and efficacy is sustained up to one year after transplantation of autologous CD34+ cells in no-option patients with chronic critical limb ischemia', Circulation, 114(18 Supplement): II-264 Abstract.
Kawamoto, A., et al. 2009. 'Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial', Stem Cells, 27: 2857-64.
Lo, B. C., et al. 2017. 'Loss of Vascular CD34 Results in Increased Sensitivity to Lung Injury', Am J Respir Cell Mol Biol, 57: 651-61.
Losordo, D. W., et al. 2011. 'Intramyocardial, autologous CD34+ cell therapy for refractory angina', Circ Res, 109: 428-36.
Losordo, D. W., et al. 2012. 'A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia', Circ Cardiovasc Interv, 5: 821-30.
Losordo, D. W., et al. 2007. 'Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial', Circulation, 115: 3165-72.
Ohtake, T., et al. 2018. 'Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb Ischemia: A Prospective Phase II Clinical Trial', Stem Cells Transl Med, 7: 774-82.
Pan, Y., et al. 2020. 'Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): a study of 63 patients in Wuhan, China', Eur Radiol.
Taguchi, A., et al. 2004. 'Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model', J Clin Invest, 114: 330-8.
Tian, S., et al. 2020. 'Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer', J Thorac Oncol.
Varga, Z., et al. 2020. 'Endothelial cell infection and endotheliitis in COVID-19', Lancet.
Xie, J., et al. 2020. 'Critical care crisis and some recommendations during the COVID-19 epidemic in China', Intensive Care Med.
Xu, X., et al. 2020. 'Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2', Eur J Nucl Med Mol Imaging.
Yang, Y., et al. 2020. 'The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China', J Autoimmun: 102434.
Zhou, F., et al. 2020. 'Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study', Lancet.
Zhu, L., et al. 2020. 'Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression', Am J Transplant.