Royalty Report: Drugs, Cancer, Pharmaceuticals – Collection: 3522

License Grant

Licensee was granted an exclusive license for the use of a family of U.S. and European patents and patent applications relating to CF101, CF102 and other small molecules and for the use, sale, production and distribution of products derived from such patents around the world. Licensor is a national research organization.

License Property

CF101 and CF102 are being developed to treat several autoimmune-inflammatory, oncological and ophthalmic indications. They are synthetic A3AR agonists. A3ARs have significant expression in tumor and inflammatory cells, whereas normal cells have low or no expression of this receptor. The A3AR agonists and allosteric modulators bind with high selectivity and affinity to the A3ARs and upon binding to the receptor initiate down-stream signal transduction pathways resulting in apoptosis, or programmed cell death, of tumors and inflammatory cells and to the inhibition of inflammatory cytokines. Cytokines are proteins produced by cells that interact with cells of the immune system in order to regulate the body’s response to disease and infection. Overproduction or inappropriate production of certain cytokines by the body can result in disease.

License Grant

Pursuant to an acquisition agreement, the Party entered into a License Agreement, in which Can-Fite granted the Licensee a sole and exclusive worldwide License for the use of CF101.

License Property

CF101 (known generically as IB-MECA), is being developed to treat three ophthalmic indications dry eye syndrome; glaucoma and uveitis. We are currently (i) conducting a Phase III trial with respect to the development of CF101 for dry eye syndrome, under an Investigational New Drug, or IND, application with the United States Food and Drug Administration, or FDA; (ii) conducting a Phase II trial with respect to the development of CF101 for the treatment of glaucoma; and (iii) preparing for Phase II study of the development of CF101 for uveitis.
CF101 is a highly-selective, orally bioavailable small molecule synthetic drug, which targets the A3 adenosine receptor (A3AR). We believe that CF101 has a favorable safety profile and a potent anti-inflammatory activity, mediated via its capability to inhibit the production of inflammatory cytokines, such as TNF-a, MMPs, IL-1, and IL-6. This is mediated by activation of the A3AR, which is highly expressed in inflammatory tissues in contrast to normal tissues where expression levels of the receptor are very low. We believe that the anti-inflammatory and neuroprotective effects of CF101 make it an attractive candidate for use in the treatment of a variety of ophthalmic diseases.

Field of Use

The field of ophthalmic diseases.

License Grant

The Licensee exclusively licensed certain patents related to EphA3 from the Licensor, that formed the basis for the KB004 program.

License Property

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene.  

Anti-EphA3 has shown encouraging preclinical proof-of-concept results in multiple tumor models. The xenograft studies we conducted show that the anti-EphA3 antibody causes growth inhibition in EphA3-positive tumors, as well as in tumors that do not express EphA3 (the latter presumably through the effect on tumor vasculature).

Cancer cells are killed by KB004 binding to EphA3 through apoptosis, or ADCC, at relatively low concentrations. KB004 ex vivo selectively targets and kills leukemic stem cells, but not normal hematopoietic stem cells. In ex vivo assays of these cells, KB004 appears to kill
all cells expressing EphA3.

Field of Use

Under the agreement, the Licensee has rights to develop human antibodies that bind to or modulate EphA3.

License Grant

Licensor grants an exclusive license, including the right to grant sublicenses, under the Licensed Patent Rights and Licensed Technology and Licensors interest in any Improvements, subject at all times to the restrictions and obligations under a Stanford Agreement with respect to the Stanford IP, to research, develop, test, obtain Regulatory Approval for, make, have made, use, have used, sell, offer for sale, have sold, import, have imported, export and have exported Licensed Products, including, without limitation, any Dimerizer included or utilized therein, in the Territory, for any and all uses within the Licensed Field during the Term, and to make, have made, use, import and export, in each case solely for research purposes, including pre-clinical IND-enabling toxicology and other pre-clinical studies, but not to conduct clinical trials with respect to or to obtain Regulatory Approval for, sell or commercialize, Licensed Products, including, without limitation, any Dimerizer included or utilized therein, for any indication other than the Primary Indications until the end of the Expansion Period and, if Licensee elects to add Additional Indications to the Licensed Field during the Expansion Period, for any indication other than the Primary Indications and the Additional Indications until the end of the Non-Cancer Expansion Period.

This agreement includes a non-exclusive grant back from Licensee to Licensor.

License Property

Licensor is the owner of or otherwise controls certain proprietary Licensed Patent Rights and Licensed Technology.

Licensors Dimerizer shall mean the compound known as xx1903, all analogs and derivatives of xx1903 and any Dimerizcr or salt thereof, where the composition of matter thereof or its use as a divalent ligand is, at any time during the Primary License Term, within the scope of a claim in any patent or patent application within the Licensed Patent Rights.

xx1903 is for the treatment of GvHD as an orphan drug.

GvHD shall mean a clinical condition involving acute or chronic adverse effects or symptoms resulting from the allogenic transplantation of bone marrow, hematopoietic or stem cells into a human being in which engrafted donor cells attack the patients organs and tissues which can be treated by activating cell signaling leading to apoptosis of the transplanted cells.

Cell Transplantation Indication shall mean GvHD or any other acute or chronic adverse clinical effect in a human being resulting from transplantation of bone marrow, hematopoietic or stem cells that can be treated by inducing apoptosis of transplanted cells, or in the case of a bone marrow, hematopoietic or stem cell product for transplantation that includes cells containing a gene coding for an Inducible Caspase, any disease or condition in a human being that can be treated by such product.

Licensed Products include  BPX-101 (formerly BP-GMAX-CDJ) , and, CaspaCIDe Donor Lymphocyte Infusion.

Field of Use

Licensed Field shall mean the treatment or prevention of the progression or occurrence in humans of any Primary Indication and/ or any Additional Indication, such as kidney cancer, or any noncancer indication, as the case may be.

Licensee is developing cell therapies to treat cancers and other chronic and life-threatening diseases.

License Grant

The Licensor hereby grants to the Licensee an exclusive license under the Licensed Rights to under the Licensed Property.  The Licensee has a unique opportunity to accelerate our development by utilizing intellectual property, drug leads, new research technologies, technical know-how and original scientific concepts derived from 25 years of research achievements relevant to cancer by licensed patent applications and patents.

License Property

CCF Technology shall mean all CCF’s unpatented inventions, know-how, trade secrets, analysis, discoveries, techniques, methods, clinical and other data, and other intellectual property relating to the research of Doctor or arising out of or in direct connection with work of Doctor in the field of regulating cell death (I) curing cancer treatment side effects by differential modulation cell death / survival mechanisms uniquely deregulated in cancer cells; (ii) selective sensitization of cancer cells to treatment by using the same approach; (iii) using anti-apoptotic proteins secreted by microbial parasites to cure tissue damage associated with cancer treatment, inflammation and other pathologies (stroke, heart attack).

Provisional Patent Application 60/526,538 – Methods of Inhibiting Apoptosis Using Latent TGFβU.S. Provisional Patent Application 60/526,666 – Methods of Identifying of Modulators of Apoptosis From Parasites and Uses Thereof U.S. Provisional Patent Application 60/526,496 – Methods of Inhibiting Apoptosis Using Inducer's of NF-kB U.S. Provisional Patent Application 60/526,667 – Methods of Inhibiting Apoptosis Using Latent TGFβU.S. Provisional Patent Application 60/526,460 – Methods of Protecting Against Radiation Using Inducer's of NF-kB U.S. Provisional Patent Application 60/526,461 – Methods of Protecting Against Radiation Using Flagellin U.S. Provisional Patent Application 60/571,149 – Small Molecules Inhibitors of MRP1 and Other Multi drug Transporters U.S. Provisional Patent Application 60/589,637 – Activation of p53 and Inhibition of NF-kB for cancer treatment.

Field of Use

Licensed Field shall mean shall mean the practice, production, manufacture, sale and use of the Licensed Rights for the discovery, development and commercialization of methods, techniques, devices, systems, animals and therapeutics in the field of regulating cell death

CBLC100 series small molecules that restore the activity of p53 tumor suppressor in cancers, including renal cell carcinomas, sarcomas, prostate cancers and other types of malignancies; curaxines and derivatives thereof are representative examples of this category;
CBLB101 series substances of biological nature (i.e., cytokine, chemokines and other secreted molecules) and their bioactive derivatives produced by tumor cells and capable of modulating cell survival; TGFß2 and derivatives thereof and derivatives thereof are representative examples of this category;
CBLB501 series natural factors produced by extracellular parasites and symbiont of humans and other mammalian species and their bioactive derivatives capable of modulating cell survival mechanisms of host cells; flagellin of Salmonella typhimurium and derivatives thereof are representative examples of this category;
CBLC500 series small molecules modulating tumor and normal cell sensitivity to cytotoxic chemicals by altering activity and substrate specificity of multi drug transporters; inhibitors of MRP1 and derivatives thereof are representative examples of this category.

License Grant

The amendment to the terms of the original collaboration agreement, among other things, converts the GITR and OX40 programs from profit-share to royalty-bearing programs.  In addition, the profit-share programs relating to two undisclosed targets were removed from the collaboration, with one reverting to Licensee and one to Licensor (the latter being the TIGIT antibody program).  The remaining three royalty-bearing programs in the collaboration targeting TIM-3, LAG-3 and one undisclosed target remain unchanged, and there are no more profit-share programs under the collaboration.

The original agreement entered into a broad, global alliance with the parties to discover, develop and commercialize novel immuno-therapeutics using the antibody platforms. The collaboration was initially focused on four CPM programs targeting GITR, OX40, TIM-3 and LAG-3, and in November 2015, was expanded by adding three novel undisclosed CPM targets.

License Property

The Licensor is a clinical-stage immuno-oncology (I-O) company focused on the discovery and development of therapies that engage the body’s immune system to fight cancer.

GITR is an immune checkpoint agonist, one of a class of receptors that amplify the immune system’s response to cancer. GITR (glucocorticoid-induced TNFR-related protein) is a receptor expressed on select populations of T cells. Activation of GITR leads to a more powerful anti-tumor inflammatory response, increased production of inflammatory signaling molecules and increased resistance to immunosuppression.

OX40 (also known as CD134 and TNFRSF4), a member of the TNFR super-family, is an immune-response-enhancing receptor found on activated T cells. OX40 promotes proliferation of these activated T cells and prevents the immunosuppressive activity of inhibitory T cells. We believe that antibodies that activate OX40 may help increase immune system activity through both of these mechanisms. Furthermore, OX40 antibodies have the potential to work alone or in combination with other therapeutics. Combining with another agonist checkpoint antibody, which provides different, yet complementary signaling attributes may further augment anti-tumor responses.

Field of Use

Checkpoint antibodies effect the immune system, and are now being used in cancer treatment.

License Grant

We restructured our product development collaboration with the Licensee, which involves six development programs including the HCD122 program. In exchange, the Licensee has control over the HCD122 program and the additional ongoing program, as well as the right to expand the development of these programs into additional indications outside of oncology.

License Property

HCD122 is a fully human anti-CD40 antagonist antibody intended as a treatment for B-cell mediated diseases, including malignancies and autoimmune diseases, is currently recruiting patients for a Phase 1/2 lymphoma trial. The antibody has a dual mechanism of action that involves inhibition of CD40-ligand mediated growth and survival while recruiting immune effector cells to kill CD40-expressing tumor cells through a process known as antibody-dependent cellular cytotoxicity (ADCC). CD40, a member of the tumor necrosis factor, or TNF, family of antigens, is a cell surface antigen expressed in B-cell malignancies and involved in a broad variety of immune and inflammatory responses.

License Grant

Licensor grants a nonexclusive license under the Licensed Patents during the Term to make, and have made, use, sell, offer for sale, and import Licensed Product in the Territory in the Field of Use.

License Property

Licensor owns and controls certain patent rights relating to methods and compositions in the field of antibodies.

Antigen shall mean Tumor Necrosis Factor alpha.

Licensed Product shall mean any product containing an Antibody related to this agreement.

U.S. patents are commonly known as the “Cabilly” patents. The Cabilly patents cover key steps of therapeutic antibody manufacturing methods. One of the Cabilly patent covers a process for producing an immunoglobulin molecule (Ig) in a single host cell; the second Cabilly patent covers a method for making an antibody heavy chain and antibody light chain in a recombinant host cell.

Field of Use

Cabilly patents are  to manufacture, use and commercialize products containing antibodies that bind to TNF-a.

Tumor necrosis factor, or TNF, belongs to a family of soluble protein mediators, or cytokines, that play an important role in disease progression across a number of inflammatory and chronic conditions, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s Disease, psoriasis and ulcerative colitis. Cytokines, such as TNF, are substances produced by cells in the body that can cause a biological effect on other cells in the body. TNF is generally understood as the “master regulator” of the body’s immune response and is the key initiator of immune-mediated inflammation in multiple organ systems. Several biologic agents have been developed that inhibit the inflammatory activity of TNF in the context of these diseases, which are collectively referred to as the anti-TNF class of therapeutics.