Scientists at the University of Minnesota Masonic Cancer Center have received notification from the U.S. Food and Drug Administration (FDA) that they can proceed with their planned combination Phase I/Phase II clinical trial for OXS-1550 (also known as DT2219ARL), a novel therapy for the treatment of leukemia and lymphoma. The drug is being developed in collaboration with Oxis Biotech, an immuno-oncology focused company holding the worldwide exclusive rights to develop and commercialize the new drug.

OXS-1550 is a bispecific scFv recombinant fusion protein composed of the variable regions of the heavy and light chains of anti-CD19 and anti-CD22 antibodies and a modified form of diphtheria toxin as its cytotoxic drug payload.  The novel trial drug targets cancer cells expressing the CD19 receptor or CD22 receptor or both receptors. OXS-1550 has demonstrated success in early human clinical trials in patients with relapsed and refractory B-cell lymphoma or leukemia.

The membrane glycoprotein CD19, present on the surface of all stages of B lymphocyte development (and is also expressed on most B-cell mature lymphoma cells and leukemia cells), plays an important role in clinical oncology. [1] In normal, healthy, cells, CD19 is the most ubiquitously expressed protein in the B lymphocyte lineage. Expression of CD19 is induced at the point of B lineage commitment during the differentiation of the hematopoietic stem cell, and its expression continues through preB and mature B cell differentiation until it is finally down-regulated during terminal differentiation into plasma cells. [1] Because CD19 expression is maintained in B-lineage cells that have undergone neoplastic transformation, and it is useful in diagnosis of leukemias and lymphomas using monoclonal antibodies and flow cytometry. [1]

CD22 is a 135-kd B-cell restricted sialoglycoprotein expressed on B-lineage lymphoid precursors, including precursor B acute lymphoblastic leukemia, and often is co-expressed with CD19 on mature B-cell malignancies. [2]  Scientists have shown that in humans, the vast majority of Immunoglobulin M (IgM) and Immunoglobulin D (IgD) B cells express cell-surface CD22, while in lymphoid tissues CD22 expression is high in follicular mantle and marginal zone B cells and weak in germinal center B cells. Furthermore, in B-cell malignancies, CD22 expression ranges from 60% to 80% depending on the histological type and on the assays used. [2]

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Dual targeting also has the advantage of delivering twice the therapy to cells that are both CD19 and CD22 expressers.

Cytotoxic payload
OXS-1550 targets cancer cells expressing the CD19 receptor or CD22 receptor or both receptors. When OXS-1550 binds to cancer cells, they internalize OXS-1550 and are killed due to the action of drug’s cytotoxic payload.

Clinical trials
In a Phase I clinical trial conducted by Oxis’ collaborators at the University of Minnesota Masonic Cancer Center, 25 patients with chemotherapy refractive B-cell lymphoid malignancies expressing CD19 and/or CD22 were enrolled. Patients with advanced drug refractory disease failed three prior types of chemotherapy, and eight failed hematopoietic transplantation.

In this trial, all patients received a single course of OXS-1550 consisting of 4 daily injections with no other treatment. Therapeutic dosing was achieved in the final 10 patients treated at the highest dose levels. Of these 10 patients, one patient with chronic lymphocytic leukemia achieved a partial response and a marginal zone lymphoma patient achieved a complete response that has now lasted more than a year and a half.

The continued trial is designed to complete the Phase I trial, determine the maximum tolerated dose (MTD), and then transition into a Phase II study permitting added cycles of treatment mandatory for durable responses. [3]

Results published in the 2015 edition of the peer-reviewed journal Clinical Cancer Research confirmed that the most common toxicity in the last 10 patients were peripheral edema and hypoalbuminemia. These toxicities were managed and reversible after a week. The authors of this study also determined that the safety of a novel immunotoxin and established its biologically active dose between 40 and 80 μg/kg/day ×4. [4]

Multiple cycle drug therapy
“We are looking forward to commencing the combination Phase I/Phase II study which we feel will clearly show the advantage of multiple cycle drug therapy,” noted the developer of the drug, Daniel A. Vallera, Ph.D, Professor, Department of Therapeutic Radiology at the University of Minnesota, who specializes in the design and development of new anti-cancer biologic agents. “We can now give twice the number of drug injections as before, and when responses are observed, we are now cleared by the FDA to give additional cycles. This drug is a powerful alternative to chemotherapy since many patients fail chemotherapy or reach the toxic limits of their chemotherapy. It is urgently needed in the clinic,” Vallera added. [5]

“We are pleased that the FDA has now given us clearance to move forward with our Phase I/II clinical trial of OXS-1550,” said Anthony J. Cataldo, Chairman and CEO of Oxis Biotech. “We believe OXS-1550 holds great promise and represents a major milestone for Oxis,” Cataldo concluded.

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