B cell precursor acute lymphoblastic leukemia (BCP-ALL or ALL) is a challenging hematologic malignancy with significant unmet medical need. More than 6000 patients are diagnosed with ALL each year in the US and Canada. About half of ALL patients are adults and half are children, which makes this leukemia the most common type of childhood leukemia.
Pre-BCR Antibodies for Leukemia
Pascal is developing antibodies against the pre-B cell receptor (pre-BCR) for ALL. The cell surface pre-BCR is expressed only by the leukemia cells and by normal pre-B cells, which represent a very early stage of B cell development. Therefore, targeting this molecule will specifically eliminate the tumor cells but spare mature activated and memory B cells that are essential for combating infection. Pascal’s lead pre-BCR antibody binds the target with high affinity, has biophysical properties consistent with expedient drug development, and is internalized into the leukemia cells upon binding the target. This latter feature presents an opportunity to create a therapeutic antibody-drug conjugate, a construct that harnesses the antibody to usher a cytotoxic agent directly into the leukemia cell. This targeted delivery eliminates the threat such agents would otherwise pose to normal healthy cells. Pascal has filed for international patent protection for this innovative technology.
In 2021, Pascal was awarded an R21 grant of $321,406 from the National Cancer Institute (NCI) of the US National Institutes of Health (NIH). The award acknowledges the potential of Pascal’s novel leukemia antibodies and the research plans detailed in the grant application titled “Eliminating B Cell Precursor Acute Lymphoblastic Leukemia by Targeting the Uniquely Specific Pre-B Cell Receptor”. The grant covers both research and administrative costs for the program over a period of two years, funding experiments to validate a lead pre-BCR antibody-drug conjugate for advancement into clinical development.
In parallel with the antibody-drug conjugate strategy, Pascal and the Korean company, Y-Biologics, have signed a collaborative research agreement for the design and development of novel bispecific antibodies to recruit effector T cells to the leukemia cells. Under the terms of the agreement, Y-Biologics is contributing its novel bispecific antibody platform technology, ALiCE, and Pascal is contributing its pre-BCR antibodies to the partnership. The two companies are sharing responsibility for the discovery and validation of lead bispecific antibody candidates and the pursuit of an optimal development path.
About B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
ALL arises as a consequence of dysregulated proliferation of early-stage B cells, which normally would mature into the B lymphocytes responsible for generating antibodies against infectious organisms. ALL is treated initially with chemotherapy, which can be quite effective at inducing enduring remission, but which does so at the cost of devastating short- and long-term side effects that include impaired childhood development and secondary cancers decades later. Patients that relapse are treated with targeted agents that can destroy the leukemia cells but also eliminate the normal, antibody-producing mature B lymphocytes, leaving patients vulnerable to infection. Pascal’s antibodies target a cell surface protein – the pre-BCR – found only on the ALL cells and on the early-stage cells from which ALL originates. This specificity distinguishes the Pascal antibodies from other targeted therapies for ALL, with the significant advantage of sparing the normal, mature B lymphocytes needed for protecting the patient from infection. Pascal’s antibodies also have the potential to reduce or eliminate reliance upon chemotherapy, thus avoiding the very difficult adverse effects of such treatment.