Development of AB-110: genetically-modified endothelial cells plus expanded cord blood hematopoietic stem cells as a transplantation therapy

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Grant Award Details

Grant Type:

Late Stage Preclinical Projects

Grant Number:

CLIN1-08342

Investigator(s):

Name:

Dr. Paul W Finnegan

Institution:

Angiocrine Bioscience, Inc.

Type:

Disease Focus:

Blood Cancer, Cancer

Human Stem Cell Use:

Adult or Tissue Stem Cell

Award Value:

$3,797,117

Status:

Closed

Progress Reports

Reporting Period:

Operational Milestone #1

Reporting Period:

Operational Milestone #2

We are developing a new stem cell transplant product, AB-110, to treat life-threatening, high risk blood cancers, such as lymphoma and leukemia. AB-110 is composed of human umbilical cord blood derived hematopoietic stem and progenitor cells co cultured and expanded with Angiocrine's proprietary E-CEL UVEC cells. The early studies demonstrating the feasibility of this approach in animal models used product derived from small scale cell co-culture in tissue culture flasks. To manufacture the product at a scale suitable for treating patients, we devised a process that uses a closed system bioreactor that can rapidly produce sufficient material with minimal human intervention. This process is both economical and reliable. Our objective in the past quarter was to optimize this manufacturing process and to demonstrate, both in cell culture assays and in animal models, that the product generated in the bioreactor is comparable to the product generated in tissue culture flasks. We have now achieved a process to reliably manufacture the E-CEL UVEC cells in the closed, automated mini-bioreactor system, that will be utilized for clinical and likely commercial production. In addition, we systematically explored the many variables in the co-culture process and ultimately succeeded in demonstrating that we could reproducibly expand umbilical cord stem and progenitor cells over hundred fold, to numbers similar to what is expected of cell numbers from adult sources, and within two weeks or less, which is regarded by transplant physicians as a time frame that would be compatible with clinical practice. We then succeeded in demonstrating that cells derived from the two processes are indistinguishable in their cellular composition, their content of stem and progenitor cells as measured by flow cytometry and colony forming assays. With the milestone of E-CEL UVEC release for GLP material produced in a GMP facility achieved, AB-110 is now being tested towards completion of IND-enabling pre-clinical studies required by the US FDA prior to entry into clinical trials.

Reporting Period:

Operational Milestone #3

Angiocrine Bioscience, Inc. has recently completed several IND-enabling preclinical studies for its experimental stem cell therapy, AB-110. The studies were funded by a grant award from the California Institute for Regenerative Medicine. AB-110 consists of E-CEL UVEC™ cells, which are engineered human endothelial cells obtained from umbilical cord tissue. Angiocrine’s proprietary technologies enable these cells, which are normally difficult to grow, to be produced at clinical and commercial scales. The E-CEL UVEC cells can multiply blood stem cells outside the body. That is because E-CEL UVEC cells mimic a natural process in the body called the ‘stem cell vascular niche’ where endothelial cells nurture, grow and instruct stem cells. Angiocrine is culturing E-CEL UVEC cells with cord blood stem cells outside the body and multiplying the latter to make AB-110. Because cord blood stem cells come in very small amounts, multiplying these stem cells with E-CEL UVEC cells can potentially provide a larger dose, and that may lead to a more effective and safer stem cell therapy. With many ‘expansion’ technologies, growing stem cells causes them to lose their quality. However, since E-CEL UVEC cells mimic the natural process found in the human stem cell vascular niche of bone marrow, E-CEL UVEC cells can multiply blood stem cells without loss of quality. AB-110 is first being studied in patients who have life-threatening blood and bone marrow cancers. AB-110 is designed to rebuild a new blood and immune system for the treated patient. The new blood and immune system not only would help the patient recover and live a normal life again but would also fight against any recurrence of the cancer. Hence, AB-110 is potentially curative.

The pre-clinical safety studies, which the FDA recommends for all cell therapies of this nature prior to entering a human clinical trial, have been successfully completed to the satisfaction of Angiocrine Bioscience and the FDA. Specifically, the toxicology studies consisted of two studies, one evaluating AB-110 and the other just the E-CEL UVEC cell component of AB-110. Across both murine studies, there were no test article-related deaths, clinical observed adverse reactions, hematological abnormalities, clinical chemistry findings, or changes in organ weight parameters.

Because E-CEL UVEC cells are genetically engineered, the capacity for generating tumors by either E-CEL UVEC cells alone or AB-110 was thoroughly tested. No tumor growth was seen in any animals injected with E-CEL UVEC cells alone or as part of AB-110 (E-CEL UVEC plus stem cells). Furthermore, the E-CEL UVEC cells were meticulously tracked in multiple biodistribution studies with an advanced molecular biology technique called qPCR which quantitatively measures genetic material at a molecular level. The E-CEL UVEC cells within AB-110 were found to be rapidly cleared, most within days after injection. These formal evaluations are in agreement with ten years of published basic science research on the safety profile of this cellular platform.

These pre-clinical studies were also supplemented with various analytical tests regarding the sterility of the materials used to generate this cell therapy as well as a highly specialized test to detect existence of any pathogens (e.g., unintended virus infection of cells). Collectively, Angiocrine Bioscience has completed animal and analytical tests demonstrating that AB-110, and E-CEL UVEC cells alone, have a safety profile appropriate to advance to testing via clinical trials in patients who have life threatening blood and bone marrow cancers.

Grant Application Details

Application Title:

Development of AB-110: genetically-modified endothelial cells plus expanded cord blood hematopoietic stem cells as a transplantation therapy

Public Abstract:

Therapeutic Candidate or Device

CD34+ Cord-Blood Derived Hematopoietic Stem and Progenitor Cells Co-Cultured and Co-Infused with Genetically Modified Endothelial Cells

Indication

Life-threatening high-risk hematologic malignancies including leukemia and lymphoma

Therapeutic Mechanism

Appropriately matched cord-blood derived stem and progenitor cells which has a significant population of both short- and long-term stem cells (expanded by genetically modified endothelial cells) rebuild the immune system after treatment called myeloablation (usually radiation and chemotherapy, also called conditioning) which destroys cancer in the blood system and bone marrow

Unmet Medical Need

For life threatening high risk blood cancer, cord blood stem and progenitor cell transplantation can be obtained rapidly and can provide a chance of cure; however, the cord blood units are small and have low cell dose, which prolongs recovery with a high chance for serious complications, even death.

Project Objective

Complete preclinical studies and file an IND

Major Proposed Activities

Develop and validate the GMP process for manufacturing the AB-110 product in a closed system bioreactor
Complete assessment of the safety of the E-CEL HUVEC component of AB-110 in both rodents and nonhuman primates as recommended by the US FDA
Prepare and file an IND application to advance the product into clinical studies

Statement of Benefit to California:

In California, blood cancers affect 19,000 patients per year with an annual mortality of 7,000 and health care costs of estimated $2.1 billion. We expect the development plan proposed in this grant will lead to a novel therapeutic approach that offers patients, in California, an effective, safe, and, importantly, curative option for the treatment of debilitating blood diseases such as leukemia and lymphoma, and potentially other serious genetic diseases affecting up to 6% of Californians.