With the support of more than $9 million dollars in Small Business Innovation Research (SBIR) grants from both the National Institutes of Health (NIH) and the National Cancer Institute (NCI) since its inception, Florida-based Altor BioScience Corporation is advancing the discovery and development of high-value, targeted immunotherapeutic agents for the treatment of cancer, viral infection, and inflammatory diseases. Most recently, Altor has been using funding from a $3 million NCI SBIR Bridge grant to support clinical development of ALT-801, an immunotherapeutic for treatment of p53-positive cancers – representing a significant opportunity to advance cancer care for many patients.
In fact, given that p53 is mutated and overexpressed in roughly 50% of all human malignancies, the potential patient population for this therapy is large. Furthermore, it is possible that more than 300,000 U.S. cancer patients could benefit each year from effective therapeutics targeting p53 positive tumors. Yet, according to Altor’s Chief Business Development Officer, Dean Taylor, Ph.D., “It is highly unlikely that this product could have been developed without SBIR funding.”
Altor’s efforts to attract the private investment needed to move their immunotherapeutic, ALT 801, toward commercialization were met with significant challenges. The company’s pipeline of products in clinical development includes monoclonal antibodies in mid-late stage trials, as well as targeted immunotherapeutics created using Altor’s novel single chain T cell receptor (scTCR) technology platform, an innovation which promises to enhance the efficacy and reduce the toxicity of existing drugs by targeting a wide range of tumor and viral antigens. However, while monoclonal antibodies are readily accepted by investors as targeted immunotherapeutics, the use of T cell receptor-based targeted immunotherapeutics is novel and their clinical utility has not been previously demonstrated.
As a result, the novelty of this approach contributed to early skepticism from investors as to the practicality of using TCRs for targeting, underscoring the importance of NCI’s SBIR funding. As Dr. Taylor explained, in addition to providing the funding for the early stages of drug development, Altor’s major venture capital investor, Sanderling Ventures, a U.S.-based leading and highly successful bioventure firm, “confirmed that the validation of Altor’s scTCR program by NCI SBIR funding played a pivotal role in their decision to invest in Altor.”
ALT 801, a tumor-targeted scTCR/IL-2 fusion protein, represents a replacement for a current tumor treatment, interleukin 2 (IL-2). As such, the market potential for ALT 801 is more than $600 MM in the currently approved indications (melanoma and renal cell carcinoma) and potentially more than $10 billion when expanded to all p53-positive cancers. Thus far, Altor has used Bridge grant funding to start a Phase II clinical trial for ALT-801 in combination with Cisplatin (a chemotherapy drug) for outpatient treatment of metastatic melanoma. Phase II trials are being planned for prostate, head and neck, bladder and renal cancers.
While Altor has advanced candidates with promising efficacy and safety data into Phase II clinical trials, much of this work would not have been possible without SBIR funding and support. Since its inception, Altor has received 11 SBIR Phase I and three SBIR Phase II grants from the NIH totaling in excess of $5 million, in addition to the $3 million Bridge grant. This funding has enabled Altor to advance its proprietary technology toward commercialization.
Further product development has been enabled through third-party funding, a result of validation by NIH’s peer-review system. This has led to the demonstration of proof-of-principal, completion of the company’s proprietary technology platforms, securing intellectual property, development of first-in-class products, and to advancement of lead therapeutic molecules into clinical trials. More specifically, completion of the non-clinical studies and clinical material manufacturing of ALT-801, also funded in part by SBIR grants, has enabled Altor to receive IND approval to initiate clinical studies. Altor has since completed a self-funded Phase I/IIa clinical trial of ALT-801 in patients with metastatic malignancies (clinicaltrials.gov identifier: NCT00496860) and has successfully initiated follow-up Phase II clinical studies (clinicaltrials.gov identifier: NCT01029873) with support of the NCI SBIR Bridge grant award. Additionally, T-cell receptor (TCR)-based reagents, developed under SBIR Phase I grant 1R43CA105816-01, have been launched as novel research reagents for validating and quantifying disease-related peptide antigens. Altor is currently developing additional HIV- and HCV-specific TCR reagents to expand this product line. Finally, Altor is collaborating with Genentech on a novel antibody against human tissue factor and in early 2009 started a Phase II clinical trial with this product for treatment of patients with Acute Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI). This project is supported by SBIR Phase II grant 1R44HL082397.
The long-term objective of the project supported by the NCI SBIR Bridge grant is to develop a tumor-targeted TCR/IL-2 fusion protein, ALT-801, as an immunotherapeutic for treatment of p53-positive cancers. The TCR portion of this fusion protein is specific for a peptide derived from the tumor-associated protein p53 presented in the context of HLA-A*0201. This high-affinity TCR is designed to guide the approved anti-cancer drug, IL-2, to the tumor site to enhance the IL-2 anti-tumor activity and to minimize toxicity associated with IL-2 treatment.
In a number of tumor models, ALT-801 inhibited the growth or caused regression of primary tumors derived from p53-positive and HLA-A*0201-positive cancer cells and exhibited significantly better anti-tumor activity than IL-2 alone. Mechanism-of-action studies suggest that the fusion protein binds to cells of the immune system and guides these cells to the tumor site where they perform their anti-tumor activities. Based on these results, ALT-801 was advanced into a Phase I/IIa trial for the treatment of cancer patients with metastatic p53-positive malignancies to evaluate the safety, immunogenicity, and pharmacokinetic profiles and to establish the maximum tolerated dose level (MTD). The fusion protein’s ability to stimulate immune cells and the level of anti-tumor activity were also measured. Patients were enrolled in three different dose level cohorts and the MTD was determined. ALT-801 was found to be well-tolerated at the MTD level. Data from the treated patients also indicate that ALT-801 lasts substantially longer in the blood (serum half-life of, ~3.3 hr) than IL-2 and achieves the corresponding targeted serum levels. ALT-801 treatment was found to increase the serum concentration of IFN?, an anti-tumor protein, without inducing TNFa (an inflammatory protein) in patient sera. It also stimulates peripheral blood mononuclear cells, indicating activation of immune cells that may play a role in anti-tumor responses. Assessment of patients’ tumors revealed stable disease in approximately 50% of the treated patients and tumor shrinkage in some patients. Based on these findings, advancement of ALT-801 into Phase II clinical testing was warranted.
With the funding provided by the NCI SBIR Bridge grant award, Phase II trials will be conducted to continue the evaluation of ALT-801’s efficacy and safety under the conditions where tumor responses were observed in the Phase I trial. The following specific aims will be pursued: 1) generate sufficient ALT-801 clinical material to support Phase II human clinical studies; and 2) conduct Phase II human clinical trials to evaluate the efficacy and safety of ALT-801 in subjects with refractory metastatic melanoma, renal cell carcinoma, head and neck cancer, and prostate cancer. A follow-up Phase II clinical trial (clinicaltrials.gov identifier: NCT01029873) has been initiated with support of the NCI SBIR Bridge grant award to evaluate ALT-801 in combination with Cisplatin for the treatment of metastatic melanoma and is currently enrolling patients. Achievement of clinical endpoints proposed by this study will prompt an expansion of enrollment in studies to provide the data necessary for advancement of ALT-801 into pivotal clinical trials for FDA approval.
Monoclonal antibodies typically target proteins on the cell surface, but are unable to target intracellular proteins. The work funded in part by SBIR grants has enabled Altor to demonstrate that these issues are not limiting factors when using TCR-based products as therapeutics. TCR-based therapeutics enable the targeting of intracellular tumor-associated proteins such as p53. Advancement of the p53-specific TCR-based therapies into clinical development and demonstration of their clinical utility will open this approach to other validated intracellular tumor antigens as candidates for targeted immunotherapy.
Altor employees have authored a number of significant publications, which demonstrate the findings of studies on their multiple products in development. These publications help to solidify TCR-based products as potential therapeutics and will likely jumpstart new avenues of research. Three publications that describe Altor’s leading products appear below.
Presently, Altor has been issued 37 U.S. and foreign patents and has more than 51 additional patent applications pending. Furthermore, a number of sophisticated research techniques, know-how, and capabilities have been developed at Altor, providing the company with a competitive edge when engineering a variety of additional biologically active molecules.
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