Degenerative and age-related diseases include osteoarthritis, heart failure, insulin-dependent diabetes, and a host of neurodegenerative conditions, such as multiple sclerosis (MS), Parkinson’s disease and Alzheimer’s disease. Current treatments largely target the symptoms rather than the underlying causes of these diseases. Even among disease-modifying drugs, few are capable of truly reversing disease pathology by restoring damaged tissues to an earlier, healthier state. Calibr is pursuing regenerative approaches that exploit small molecule drugs to control the fate of endogenous stem cell populations. Examples include enhanced cartilage repair by chondrocytes derived from mesenchymal stem cells for osteoarthritis, and remyelination of neurons by oligodendrocytes derived from neural precursor cells for MS – both programs are in late-stage preclinical development. Earlier stage programs focus on the generation of functional cardiomyocytes, astrocytes and osleoblasts. In degenerative diseases that lack an obvious source of renewable cells, we employ approaches to regenerating functional tissue through regulated proliferation of somatic cells, such as pancreatic beta cells, and retinal pigment epithelial cells. Finally, Calibr is attempting to identify drugs that block the stress and oxidative pathways contributing to many age-related disease.
Cancer represents a group of the most prevalent and devastating diseases. Recent advances in understanding the mechanisms that underlie tumor development, maintenance, and metastasis have presented significant opportunities for the development of novel therapeutic strategies. Calibr’s small molecule oncology research leverages expertise in high-throughput phenotypic screens, medicinal chemistry, and in vivo pharmacology to identify compounds that exploit unique mechanisms. Examples include the discovery of molecules that down-regulate the oncogenic transcription factor c-Myc, differentiate or selectively eliminate cancer stem cells, or modulate the aberrant metabolism of cancer cells. Calibr’s programs target a broad range of solid and liquid tumors types.
Cancer research at Calibr is also focused on the development of next generation immunotherapeutics. Recent clinical studies have shown exciting results in the re-engagement of the immune systems’ natural anti-tumor response to potently eliminate malignancies. Calibr’s immuno-oncology research exploits these paradigm-shifting insights to develop bispecific antibodies and chimeric antigen receptor T cells (CAR-T) for AML, multiple myeloma, breast, colorectal and prostate cancer. These efforts are supported by proprietary protein and cell engineering methodology at Calibr. Examples include a novel bispecific small molecule-antibody conjugate targeting prostate cancer which is being progressed to investigational new drug (IND) status with support from the Wellcome Trust Translation Fund. Calibr has also applied its expertise in small molecule drug and protein chemistry to the development of antibody-drug conjugates that target a number of cytotoxic drugs to prostate cancer, multiple myeloma and metastatic cancers.
Rare diseases – also referred to as orphan diseases – represent some of the most debilitating, life-altering diseases and often disproportionately affect young people. Treatment options for these diseases are frequently expensive, ineffective, or target to a limited subpopulation of patients. Despite their low incidence, the etiology of these diseases is widely studied, yielding significant opportunities for early-stage translational efforts to be brought to bear on them. Calibr seeks to identify and develop novel therapies for rare diseases such as spinal muscular atrophy (SMA), cystic fibrosis (CF), and childhood leukemia’s. Supported by Cure SMA, Calibr has identified and is developing a novel small molecule that rescues the underlying protein defect in SMA patients. Through rational design, Calibr has developed a novel and safe approach to lung hydration that offers protection from secondary lung infections – the leading cause of death in CF patients. This approach is broadly applicable and is likely to benefit patients suffering from chronic obstructive pulmonary disease (COPD) and other lung diseases. Calibr is also developing therapies to complement genetic defects in orphan diseases such as sickle cell anemia, alpha-antitrypsin and growth hormone deficiency. These efforts exemplify Calibr’s unique ability as a both a drug discovery and not for profit organization to pursue unmet medical needs regardless of short-term commercial incentives.
Calibr is dedicated to the identification and development of new therapeutic approaches to treat, prevent, and eliminate disease associated with human pathogens that collectively inflict a devastating burden on global health, with a disproportionate impact on developing nations. These efforts are aimed at targeting: latent and multi-drug resistant tuberculosis via novel mechanisms; multiple life-cycle stages of malaria infection with long-acting compounds; adult filarial nematodes that cause river blindness and lymphatic filariasis; anopheles and related insect vectors that propagate malaria and other pathogens; Ebola through inhibiting viral replication. Complementary to these efforts are a number of host-targeted therapeutic approaches for several of these and for other indications including diarrheal disease, HIV, and tuberculosis. This research is facilitated in large part by a substantial partnership with the Bill and Melinda Gates Foundation that combines Calibr’s drug discovery expertise and infrastructure with leading academic research at the University of California, Cornell University, and Albert Einstein College of Medicine, where investigators have unique insights, access, and capabilities.
Metabolic and cardiovascular diseases embody a range of conditions that collectively are the leading cause of death in the developed world. Despite a host of pharmaceutical and lifestyle intervention options, the prevalence of these diseases continues to rise. In addition, metabolic dysfunction associated with diabetes and obesity can lead to non-alcoholic steatohepatitis (NASH), liver cirrhosis and cancer. Calibr is leveraging its expertise and infrastructure in phenotypic cell-based screening to identify novel therapeutic candidates that address underlying cellular pathologies, including: enhancing energy expenditure through ectopic brown fat differentiation; restoring insulin secretory capacity by promoting beta cell survival and function; altering the profile of hepatic lipoprotein output; and regenerating functional cardiac tissue through controlled proliferation of cardiomyocytes. In parallel, Calibr’s long-lived biologics and antibody-drug conjugate platforms are being brought to bear to create next-generation therapies based on the established pharmacological properties of incretins, adipokines, insulin and insulin-family cardiometabolic peptides, and hypermetabolic hormones. A partnership with the Juvenile Diabetes Research Foundation (JDRF) has enabled efforts across a range of type 1 diabetes approaches, including both beta cell and novel insulin targeted therapies. The above programs have already generated molecules with excellent preclinical in vivo activity in regulating glucose homeostasis, enhancing metabolic function, improving lipid abnormalities and improving cardiac function.
Autoimmune and inflammatory diseases represent a diverse set of pathologies with many common underlying features that lend themselves to overlapping therapeutic approaches. Calibr’s focus centers on modulating pathological immune cell responses, as well as disease progression in the affected tissue, using both high-throughput screening approach and the rational design of tissue-specific agents. For example, Calibr uses multiplex, high-content screens which leverage the plasticity of hematopoietic cells to identify novel modulators of the immune response that mitigate inflammation and tissue damage. Small molecules that block secretion of key pro-inflammatory mediators have been identified and show promise as alternatives to neutralizing antibodies. The identification of compounds that mitigate stress response in cells targeted by autoimmunity and inflammation, such as beta cells in type 1 diabetes may bolster the survival and function of target tissues in the context of worsening disease. Molecules that block cellular transdifferentiation to myofibroblasts represent a novel approach to a variety of fibrotic diseases and are in late-stage preclinical development. In addition to screening approaches, tissue-specific delivery methods are being pursued that allow potent drugs, which otherwise lack suitable systemic safety to achieve high effective exposure to resolve chronic inflammation and tissue damage. Calibr takes an opportunistic approach in deploying these strategies to a range of diseases, including inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, fibrosis, and COPD.