Oxis Biotech Inc. (Tampa, Florida, 33609)* and MultiCell Immunotherapeutics, Inc. (Woonsocket, RI 02895) announced the execution of a definitive licensing and development agreement for the development of antibody-drug conjugates or ADCs.  The new antibody-drug conjugates, based on Oxis’ lead drug candidates (OXS-4235 for Multiple Myeloma and OXS-2175 for Triple-Negative Breast Cancer) and using MultiCell’s proprietary ADC platform technology, are designed for the treatment of triple-negative breast cancer, multiple myeloma and associated osteolytic lesions which represents a significant unmet medical need.

Oxis Biotech develops innovative drugs focused on the treatment of cancer and other unmet medical needs. Oxis’ lead drug candidate, OXS-2175, is a small molecule therapeutic candidate targeting the treatment of triple-negative breast cancer. In in vitro and in vivo models of Triple-Negative Breast Cancer, OXS-2175 demonstrated the ability to inhibit metastasis. Oxis’ lead drug candidate, OXS-4235, also a small molecule therapeutic candidate targets the treatment of multiple myeloma and associated osteolytic lesions. In in vitro and in vivo models of multiple myeloma and osteoporosis, OXS-4235 demonstrated the ability to kill multiple myeloma cells, and decrease osteolytic lesions in bone.

Proprietary platform technology
MultiCell’s proprietary antibody-drug conjugate platform technology is based on unique multivalent, cleavable linkers that allow tethered drugs to be released intracellularly or extracellularly upon binding of the antibody to the target cell. Additionally, MultiCell’s linkers are designed to attach multiple drugs per targeting antibody, and to release the drugs in their original form without modification of the drug.

Triple-negative breast cancer
According to the American Cancer Society[1] there were approximately 231,840 new cases of invasive breast cancer last year in the USA and 40,290 deaths from breast cancer during the same period. Women represent 99% of all breast cancer patients. Breast cancer is treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy.

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While breast cancer is usually characterized based upon the presence of, or absence of, the ER, PR and HER2/neu receptors, triple-negative breast cancer or TNBC is a biologically heterogeneous group of breast cancers characterized by the lack of immunohistochemical expression of the ER (estrogen receptors), PR (progesterone receptors), or HER2 proteins. This means that in these patients the offending tumor lacks these receptors [estrogen receptor-negative(ER-), progesterone receptor-negative (PR-) and HER2 receptor-negative (HER2/neu-)]. Approximately 10% – 20% percent of invasive breast cancers are diagnosed as triple-negative breast cancers.

Unmet need
Depending on the stage of its diagnosis, triple negative breast cancer can be particularly aggressive, and is more likely to recur. TNBC is also less sensitive to available treatments than other forms of breast cancer. Unfortunately, despite significant advances in the targeted therapy of breast carcinoma – with development and approval drugs like trastuzumab (Herceptin®; Genentech/Roche), bevacizumab (Avastin®; Genentech/Roche) and small molecules that inhibit tyrosine kinases or PARP, the treatment of triple negative breast cancer remains an unmet medical need. With limited options, treatment typically involves non-targeted cytotoxic chemotherapies.

A number of companies are developing antibody-drug conjugates for the treatment of TNBC. In late October 2014, The Netherlands based Synthon Biopharmaceuticals started an open label clinical trial with SYD985 with patients currently indicated for HER2-targeted treatment as well as patients with HER2 2+ and HER2 1+ breast cancer for whom there currently is no effective anti-HER2 therapy available.[2]

SYD985 is a novel anti-HER2 antibody-drug conjugate or ADC which consists of a potent duocarmycin-based pro-drug (seco-DUocarmycin-hydroxyBenzamide-Azaindole or DUBA) linked via a proprietary linker that can be cleaved by tumor-resident proteases at the dipeptide valine-citrulline (vc) motif, to the monoclonal antibody (mAbs) trastuzumab, a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. If successful, this drug too could provide a new treatment option for patients with TNBC.

African American and Hispanic Patients
Triple-negative breast is more likely to affect younger people, African Americans or Hispanics, and those with a BRCA1 gene mutation.[3] This type of breast cancer is insensitive to many of the most effective therapies available for the treatment of breast cancer including the HER2-directed therapy Herceptin® (trastuzumab)**, and endocrine therapies such as tamoxifen or the aromatase inhibitors. The relapse and survival rates of triple-negative breast patients are shorter than for patients with other types of breast cancer.

Multiple myeloma
Multiple myeloma is a type of cancer that forms in white blood cells, and affects about 26,850 people annually in the USA causing about 11,240 deaths per year.[4] This disease causes cancer cells to accumulate in the bone marrow, where they crowd out healthy blood cells. Multiple myeloma is also characterized by destructive lytic bone lesions (rounded, punched-out areas of bone), diffuse osteoporosis, bone pain, and the production of abnormal proteins which accumulate in the urine.

Anemia is also present in most multiple myeloma patients at the time of diagnosis and during follow-up. Anemia in multiple myeloma is multifactorial, and is secondary to bone marrow replacement by malignant plasma cells, chronic inflammation, relative erythropoietin deficiency, and vitamin deficiency.

Plasma cell leukemia, classified as either primary (in 60% of cases) or secondary (in 40% of cases), is a rare and aggressive variant of multiple myeloma, is a condition in which plasma cells comprise greater than 20% of peripheral leukocytes or 2 x 109/L. [5][6]  With poor prognosis characterized by peripheral blood involvement, it is typically a terminal stage of multiple myeloma and is associated with short survival.

The median age of patients with plasma cell leukemia is 50-60 years with an approximately equal proportion of male and female patients. In both its primary and secondary forms, plasma cell leukemia clinically resembles late-stage multiple myeloma in which they may present with anemia, cytopenias, recurrent bacterial infections, or renal insufficiency. Osteolytic lesions and pathologic fractures occur but are less frequent. However, residual marrow function is usually more compromised. Renal failure, lymphadenopathy, and organomegaly are more frequent.

“We were pleased to add this new technology to our portfolio. Antibody-Drug Conjugates are the wave of the future. This significant technology allows us to leverage our existing platform technologies as targeted therapies which can increase better yield and efficacy as we progress our therapies through the FDA approval process,” noted Anthony J. Cataldo, Chief Executive Officer of Oxis.

Market potential
Sales of breast cancer drugs are projected to increase in nine major world markets from $9.8 billion in 2013 to $18.2 billion by 2023, according to new forecasts from IMS Health. Analysts at Visiongain, Ltd. predict the world market for multiple myeloma therapies will reach $11.5 billion in 2017.

According to FiercePharma, Celgene‘s cancer drug lenalidomide (Revlimid®) for the treatment of multiple myeloma generated nearly $5 billion in revenue for the company in 2014. Analysts believe sales of lenalidomide could double within 5 years as a result of FDA’s recent approval of expanded labeling concerning the use of lenalidomide in combination with dexamethasone for patients newly diagnosed with multiple myeloma. [7] About 93,600 patients are living with multiple myeloma in Europe and about 88,499 patients are living with it in the United States.

PDL BioPharma, Inc. stated its licensee Genentech, Inc. reported sales of trastuzumab, used in the treatment of breast cancer, totaled $7.3 billion in 2014.

“We are very excited about our novel, enabling antibody-drug conjugate technology, and are pleased to partner with Oxis Biotech to develop targeted delivery versions of their drug candidates”, noted W. Gerald Newmin, Chairman and Chief Executive Officer of MultiCell Immunotherapeutics. “We continue to explore therapeutic indications and drug combinations of interest to us, and will continue to aggressively seek partnerships with larger pharmaceutical and biotechnology companies who are interested in using our ADC technology to help facilitate the targeted delivery of their drugs,” Newmin further stated.

Development agreement
Under the terms of the agreement between the companies, MultiCell develops three antibody-drug conjugates candidates. Oxis paid MultiCell a license fee of $500,000 and will reimburse the company up to $1.125 million for its development costs to make these three trial drugs exclusively licensed to OXIS. Assuming that all clinical development milestones are achieved and manufacturing rights to the three antibody-drug conjugates purchased, Oxis will pay MultiCell an additional sum of $22.75 million and pay a royalty of 3% of net yearly worldwide sales upon marketing approval of the drugs.

The Emmes Group, a strategy consulting firm with offices in Boston, MA and San Francisco, CA, believes that if Oxis achieves all of its clinical development milestones, purchases manufacturing rights to the ADCs, and meets worldwide sales and sub-licensing expectations following receipt of marketing approval for the three antibody-drug conjugates for the treatment of breast cancer and multiple myeloma, MultiCell could expect to receive in excess of $540 million during the term of the agreement.


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