Bayhill Therapeutics is a clinical-stage biopharmaceutical company using its proprietary therapeutic BHT-DNA™ platform to develop a pipeline of novel products to treat autoimmune diseases in a fundamentally new manner. The Company’s product candidates are designed to restore the immune system to its normal state known as “tolerance,” by selectively eliminating specific, harmful immune responses while leaving the rest of the immune system intact. Through a targeted and selective approach, Bayhill’s product candidates have the potential to improve efficacy, safety and tolerability relative to current therapies.
The immune system is the major biological defense responsible for fighting pathogens and tumors by recognizing certain molecules, known as antigens. Antigens are defined as any substance that invokes the production of a specific immune response. These include proteins like MBP and proinsulin, and specific peptides that are fragments of those proteins.
A properly functioning immune system attacks foreign antigens but is tolerant to self-antigens, which are antigens present in the body’s own tissues. Autoimmune diseases occur when there is a breakdown of the mechanism responsible for tolerance that triggers the immune system to mediate an immune response against the body’s own tissues. This inability to fend off this self directed autoimmune attack results in a chronic, debilitating disease characterized by tissue destruction. Major diseases for which there is a known autoimmune component include multiple sclerosis (MS), type 1 diabetes mellitus (T1D), myasthenia gravis (MG), and inflammatory bowel disease (IBD). Antigen-specific autoimmune responses to a self-antigen are considered the primary drivers of these diseases. Effective treatments that specifically disrupt this self-antigen response with minimal side effects could potentially address the fundamental cause of an autoimmune disease while leaving the broader immune system intact.
The key components of immune response are lymphocytes, or specialized white blood cells of which there are two major types: B lymphocytes and T lymphocytes. B lymphocytes (B cells) produce the antibodies that bind to the antigen and differentiate between billions of antigens that each produce a specific antibody directed against a single antigen. T lymphocytes (T cells) are essential to B cell maturation and antibody production. They regulate the immune response through direct cell-to-cell contact whereby each T cell recognizes only a single specific antigen. T cell activation requires the concomitant presentation of two signals 1) T cell recognition of the unique antigen and 2) a secondary “co-stimulatory” activating signal resulting from exposure to pro-inflammatory compounds of certain cells in the immune system known as antigen presenting cells (APCs) , which confirms that the antigen is foreign.
Signal 1, in the absence of Signal 2, turns off the T cell response and results in tolerance. BHT-DNA™’s mechanism activates the first signal when the APC expresses the BHT-DNA™-encoded self-protein being attacked by the autoimmune response (Signal 1) in the absence of inflammation (suppression of Signal 2). As a result, the T cells that recognize the self-antigen are turned off, thus inducing tolerance.
BHT-DNA Therapeutic Platform
Bayhill’s BHT-DNA™ therapeutic platform is used to develop the Company’s lead product candidates with enhanced efficacy by modifying plasmid DNA in order to deliver the encoded self-antigens in a tolerizing context. Among the proprietary changes to plasmid DNA, Bayhill adds immunoinhibitory sequences to BHT-DNA in order to promote tolerance while removing immunostimulatory sequences, or pro-inflammatory signals, that activate the immune system.
Upon intramuscular injection, the plasmid DNA is taken up by dendritic cells, a type of APC, which then migrate to the lymph node. Inside these dendritic cells, the encoded self-antigen is expressed and processed. Peptides of the self-antigen protein are then presented on the surface of the dendritic cell for exposure to the T cell, and only those T cells that specifically recognize the presented peptide can be affected by this exposure. In the absence of invading pathogens that induce co-stimulatory factors, the APC is thought to anergize, or induce tolerance, of the specific T cells. Antibody production, which requires the presence of antigen-specific T cells, should also fall without such T cell “help.”
Bayhill’s BHT-DNA™ therapeutic platform offers a number of advantages:
• Ability to develop a robust pipeline of product candidates targeting
autoimmune diseases for which the target protein self-antigen(s) are known.
Published medical research indicates that 28 such autoimmune diseases have been identified, including MS, T1D and MG, all three of which are Bayhill’s initial indications of focus. The BHT-DNA™ platform is potentially applicable to any autoimmune disease in which the target protein self-antigen or self-antigens are known.
• Rapid creation and optimization of preclinical product candidates for diseases with known self-antigen(s).
Upon identifying a target indication with a known self-antigen, BHT-DNA™ enables the preparation of a proprietary plasmid containing the self-antigen gene for testing in a matter of days. Beyond initial testing, Bayhill’s technology is capable of rapidly modifying the plasmid to optimize its effectiveness and specificity.
• BHT-DNA™’s broad applicability allows for development of all product candidates using similar Chemistry, Manufacturing and Controls (CMC) processes.
Bayhill expects to use similar, well-established techniques for producing and purifying all of its product candidates. These techniques share common biochemical characteristics and generate consistently reproducible yields of stable bio-molecules. The Company has leveraged the CMC experience gained in developing BHT-3009 for MS in developing the CMC processes for BHT-3021 in T1D, and expects to do the same for future product candidates.
• Regulatory pathway expected to be similar for all BHT-DNA™-based product candidates.
The BHT-DNA™ therapeutic platform generates product candidates that with common attributes, such as CMC and preclinical safety testing requirements. As a result, Bayhill expects that once reviewing regulatory agencies become familiar with the technology and initial MS product candidate, they are likely to understand the T1D, MG and additional product candidates thereafter.
• Proprietary plasmids encode the entire target self-antigenic protein, thereby minimizing the risk of missing self-antigen peptides relevant to each patient.
By encoding the entire target self-antigenic protein, such as full-length MBP or proinsulin, BHT-DNA™ covers all possible peptides within that protein, increasing the likelihood of tolerizing to the relevant self-antigen(s). As a result, products based on BHT-DNA™ may show improved efficacy compared to other tolerizing approaches that target only one or a limited number of self-antigenic peptides.
• BHT-DNA™ optimizes tolerance and eliminates the need for frequent dosing through persistent low-level self-antigen expression that replicates the body’s natural processes.
Expression of the encoded self-antigen from the proprietary plasmid has been detected from two to four weeks after a single intramuscular injection. Low-level continuous exposure to an antigen appears to be essential to inducing tolerance and persistent self-antigen expression may support infrequent dosing.
Product Pipeline
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