BCMA is a surface protein that is highly expressed in multiple myeloma cells and in approximately 50% of Chronic Lymphocytic Lymphoma and Diffuse Large B-Cell Lymphoma cells to which the selected antibodies specifically bind. Based on a license with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Heidelberg Pharma has produced several proprietary ATAC® molecules and optimized and validated them preclinically. As a result, the development candidate HDP-101 has emerged as a clinical candidate.
Preclinical data showed that HDP-101 had strong anti-tumor activity and a very favorable therapeutic window. Multiple myeloma is a cancer affecting bone marrow and the third most common hematologic cancer; it represents a major unmet medical need where new, more effective therapies are urgently needed. HDP-101 also has potential in other hematologic indications.
Since February 2022, patients are enrolled in the study and dosed. Currently six trial centers are active in the USA and in Germany. Additional centers will be initiated in Europe.
HDP-102 is an ATAC® targeting CD37 that is overexpressed on B-cell lymphoma cells. HDP-102 will be developed for specific indications of non-Hodgkin lymphoma (NHL).
PSMA is overexpressed in prostate cancer and is a promising target for ATAC technology, as it shows very low expression in normal tissues.
Heidelberg Pharma has licensed several PSMA (prostate-specific membrane antigens) specific antibodies from Freiburg University.
The lead candidate HDP-103 was selected to be tested in a clinical study in metastatic castration-resistant prostate cancer (mCRPC). The therapeutic use of an Amanitin conjugate is supported by the high prevalence of a 17p deletion in mCRPC (60%). Since tumor cells with a 17p deletion are particularly sensitive to Amanitin, PSMA-ATACs may be particularly well suited for the treatment of mCRPC.
The tumor suppressor gene p53 and the gene for RNA polymerase II are located on chromosome 17. The product of the p53 gene is intended to prevent tumor formation in healthy cells. Cancer cells have changes in their genetic material in such a way that this protective function can no longer be fully exercised. This protein thus represents one of the most important control substances for cell growth and thus also a focus of oncological research. Tumors frequently loose or have mutations in the p53 gene in the tumor cells in order to weaken the cells' natural defenses. The deletion of p53 gene is almost always accompanied by the deletion of POLR2A gene as those genes are in close proximity on the short arm chromosome 17. This is known as 17p deletion. The POLR2A gene encodes the largest and essential subunit of RNA polymerase II, and the loss of POLR2A results in decreased copy number of this essential protein. Since the mode of action of Amanitin is to inhibit RNA polymerase II and eventually trigger a programmed cell death, the tumor cells with 17p deletion is particularly sensitive to Amanitin. This genetic alteration is found in many types of cancer and usually linked with more aggressive and treatment resistant forms of malignancies.
In collaboration with various research groups in Germany and the US, including Heidelberg University Hospital, the MD Anderson Cancer Center at the University of Texas, and the School of Medicine at Indiana University, preclinical studies have demonstrated that Amanitin has the potential to be particularly effective against tumors with a 17p deletion which are difficult to treat.
Heidelberg Pharma intends to explore the importance of 17p status clinically, i.e. to stratify the patient population according to their 17p status in the planned clinical trials. The presence of a 17p deletion could serve as a potential biomarker for Amanitin-based therapeutics. Heidelberg Pharma assumes that patients with a 17p deleted tumor could particularly benefit from treatment with Amanitin-based therapies.
ATACs thus represent a promising therapeutic strategy for patients suffering from highly resistant tumor diseases. In a clinical setting, the selection of patient based on TP53 and POLR2A gene status could allow the expansion of the therapeutic window, and ensure high efficacy while reduced side effects.