On April 18, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported a new set of preclinical data further validating the potential of its first-in-class anti-MICA/B antibody IPH4301 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511087]).

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Poster #1491 reports that IPH4301, a humanized antibody, binds with high affinity to MICA/B and is a potent cytotoxic antibody, inducing direct tumor cell killing by ADCC. Moreover, an additional mode-of-action of the same antibody was revealed, whereby the antibody has the potential to overcome immunosuppression in tumors.

Among the highly immune-suppressive cell types in cancer are tumor-associated macrophages or myeloid-derived suppressor cells (MDSC), which can reduce NK and T cell activities. In vitro, IPH4301 could overcome immunosuppression by macrophages, restoring NK cell antibody-mediated killing to levels seen in the absence of suppressor macrophages. In addition, IPH4301 blocked MICA/B-induced down-modulation of NKG2D receptors on NK and CD8 T cells, thus disrupting a second immuno-suppressive mechanism. Finally, treatment with IPH4301 restored NK cell infiltration, prevented tumor growth and improved survival in different in vivo tumor models.

Nicolai Wagtmann, CSO of Innate Pharma, said: "We are enthusiastic about IPH4301 as a therapeutic candidate because of its dual mode of action, combining potent ADCC-mediated tumor killing with interesting immuno-modulating properties. The ability of IPH4301 to interfere with these immune-suppressive pathways, while at the same time retaining high direct ADCC potency, makes for a novel, unique proposition in the immune-oncology landscape. IND-enabling studies will start in 2016".

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CD123 is a subunit of the heterodimeric interleukin-3-receptor (IL-3R) which is widely expressed on human hematologic malignancies including acute myeloid leukemia (AML). In addition, CD123 can be found on the surface of B cell acute lymphoblastic leukemia (B-ALL), hairy cell leukemia, blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myeloid leukemia (CML) and Hodgkin’s lymphoma.

Of these malignancies, we are currently investigating CD123 as a target for adoptive cellular immunotherapy in AML since high CD123 expression is associated with enhanced AML blast proliferation, increased resistance of blasts to apoptosis, and poor clinical prognosis.

Acute Myeloid Leukemia (AML), is a cancer of the myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in the bone marrow. AML is the most common form of acute leukemia. Although AML is a relatively rare disease there are approximately 20,000 new cases per year in the US and 10,000 deaths per year, accounting for approximately 1.8% of cancer deaths in the US (SEER). AML standard of care involves chemotherapy to induce remission followed by additional chemotherapy or hematopoietic stem cell transplant. Allogeneic stem cell transplantation is the preferred treatment route for AML following a second remission. It can lead to a 5-year disease free survival in 26% of patients. Unfortunately however, currently, only about half of relapsed patients are able to achieve a second remission with traditional chemotherapy agents. Patients who do not achieve a second remission are much less likely to benefit from transplantation and face a poor outcome.

The use of CAR-T immunotherapy in relapsed AML patients may offer the potential to achieve a complete or longer lasting remission. City of Hope developed CD123 targeted CAR-T cells designed to be both activated to proliferate and to kill CD123 expressing tumor cells. The therapy is designed to recognize and eliminate leukemic cells leading to remission in patients with relapsed or refractory AML and could serve as a bridge to potentially curative allogenic stem cell transplant. The manufacturing process genetically modifies T-cells isolated from peripheral blood mononuclear cells to express a CD123-specific, hinge–optimized, CD28 co-stimulatory domain expressing CAR as well as an EGFRt selection/safety marker. The last feature acts a safety switch to allow depletion of CAR-T cells in the patients if needed.

In collaboration with the COH, we have an on-going phase I clinical study to assess the anti-tumor activity and safety of administering CD123 targeted CAR-T cells and are currently treating patients. We will assess the T-cell persistence and determine the potential immunogenicity of the cells to determine a recommended phase II dose.

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Glioblastoma multiforme (GBM) is the most common brain and central nervous system (CNS) cancer, accounting for 15.1% of all primary brain tumors, and 55.1% of all gliomas. There are an estimated 12,120 new glioblastoma cases predicted in 2016 in the U.S. Malignant brain tumors are the most common cause of cancer-related deaths in adolescents and young adults aged 15-39 and the most common cancer occurring among 15-19 year olds in the U.S. While GBM is a rare disease (2-3 cases per 100,000 person life years in U.S. and E.U.), it is quite lethal with 5-year survival rates historically less than 10%. Chemotherapy with temozolomide and radiation are shown to extend mean overall survival from 4.5 to 15 months, while surgery remains the standard of care. GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies.

Immunotherapy approaches targeting brain tumors offer promise over conventional treatments. IL13Rα2 is an attractive target for CAR-T therapy as it has limited expression in normal tissue but is over-expressed on the surface of greater than 50% of GBM’s. CAR-T cells are designed to express membrane-tethered IL-13 receptor ligand (IL-13) with high affinity for IL13Rα2 and reduced binding to IL13Rα1 in order to reduce healthy tissue targeting.

We are developing an optimized CAR-T product incorporating enhancements in CAR design and T-cell engineering to improve antitumor potency and T-cell persistence. We include a second generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off target Fc interactions as well as the 41BB (CD137) co-stimulatory signaling domain for improved survival and maintenance of memory T-cells as well as extracellular domain of CD20 as a selection/safety marker. In order to further improve persistence, central memory T-cells (TCM) are isolated and enriched. The manufacturing process limits ex vivo expansion in order to reduce T-cell exhaustion and maintain a TCM phenotype.

In collaboration with the COH, we have an on-going phase I clinical study to assess the feasibility and safety of using TCM enriched IL13Rα2-specific CAR engineered T-cells and are currently treating patients with recurrent/refractory GBM. We will assess the T-cell persistence and determine the potential immunogenicity of the cells to determine a recommended phase II dose.

On April 18, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported data on a research program to develop a CD73 checkpoint inhibitor antibody in oncology at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511075]). This new anti-CD73 project complements Innate’s first-in-class anti-CD39 program strengthening the Company’s positioning in targeting the tumor microenvironment.

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CD73 and CD39 are two enzymes which play a major role in promoting immunosuppression through the pathway degrading adenosine triphosphate (ATP) into adenosine. CD73 is active on the last step of the degradation pathway, where it is the enzyme that actually degrades AMP* into adenosine.

Poster #2344 presented a panel of newly generated antibodies that block CD73 function. They all bind with high affinity and specificity to the CD73 enzyme, but to distinct epitopes and display different mechanisms of inhibition, including direct blocking of CD73 enzymatic activity or down-modulation of CD73 membrane expression. All antibodies strongly reduce AMP catabolism and efficiently reverse adenosine-mediated T cell suppression in vitro. The antibodies displaying the most interesting features were humanized and further evaluation of their activity is ongoing.

Nicolai Wagtmann, CSO of Innate Pharma, said: "This program adds to our innovative and diversified portfolio of checkpoint inhibitors. We are entering the very exciting and novel area of microenvironment checkpoint inhibition which complements other immuno-oncology approaches. Our anti-CD73 and anti-CD39 antibodies each have potential as single-agent therapeutics and for combination with other checkpoint blockers notably targeting T or NK cells".

On April 18, 2016 Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, reported that data from several ZFP Therapeutic programs will be presented at the 19th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) to be held in Washington, D.C. from May 4-7, 2016 (Press release, Sangamo BioSciences, APR 18, 2016, View Source [SID:1234511044]).

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Sangamo BioSciences, Inc. (PRNewsFoto/Sangamo BioSciences, Inc.)
Eight oral and seven poster presentations will be given by Sangamo scientists and their academic collaborators. These presentations will detail data from Sangamo’s therapeutic and research programs and will focus on lysosomal storage disorders and other monogenic diseases, hemoglobinopathies, HIV/AIDS, cancer immunotherapy and advancements in technology, including improvements in modification efficiency. In addition, Sangamo scientists have been invited to present in two scientific symposia focused on clinical applications of genome editing and gene and cell therapeutics targeting the liver.

"The data to be presented at this year’s ASGCT (Free ASGCT Whitepaper) Annual Meeting from our therapeutic and research programs cover a wide range of applications and demonstrate the versatility of our zinc finger nuclease genome editing platform and the expertise of our research and development teams," said Edward Lanphier, Sangamo’s president and chief executive officer. "Sangamo continues to lead the clinical development of therapeutic genome editing and ASGCT (Free ASGCT Whitepaper) offers an opportunity for us to present the broad capabilities of our highly leverageable technology platform in multiple therapeutic areas."

The following presentations are scheduled at the ASGCT (Free ASGCT Whitepaper) Meeting sessions:

Invited Presentations at Scientific Symposia

Genome Editing in Primary Human Cells and Organs: Toward the Goal of Engineering Genetic Cures – Michael C. Holmes, Ph.D., Sangamo BioSciences
Special Symposium on Concepts and Clinical Applications of Genome Editing
Invited Talk – Wednesday, May 4, 2016

ZFN-Mediated Genome Editing in the Liver – Towards Correcting Hemophilias and Lysosomal Storage Diseases – Thomas Wechsler, Ph.D., Sangamo BioSciences
Scientific Symposium: Targeting the Liver with Gene and Cell Therapeutics
Invited Talk – Wednesday, May 4, 2016

Lysosomal Storage Disorders

In Vivo Zinc-Finger Nuclease Mediated Iduronate-2-Sulfatase (IDS) Target Gene Insertion and Correction of Metabolic Disease in a Mouse Model of Mucopolysaccharidosis Type II (MPS II) – Abstract #484
Session: Targeted Genome Editing: In Vivo Genome Editing
Oral Presentation – Friday, May 6, 2016

ZFN-Mediated Liver-Targeting Gene Therapy Corrects Systemic and Neurological Disease of Mucopolysaccharidosis Type I – Abstract #485
Session: Targeted Genome Editing: In Vivo Genome Editing
Oral Presentation – Friday, May 6, 2016
HIV/AIDS

CCR5 Gene Edited Hematopoietic Stem Cells Engraft in Diverse Anatomical Locales and Undergo SHIV-Dependent Positive Selection in Nonhuman Primates – Abstract #38
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

In Vivo Inhibition of HIV-1 in NSG Mice After Transduction of Primary Human T Cells with CXCR4 Conjugated to an HR2 Peptide – Abstract #427
Session: Immunological Aspects of Gene Therapy I
Poster Presentation – Thursday, May 5, 2016

Pre-Clinical Development and Qualification of ZFN-Mediated Disruption of CCR5 Gene Sequences in Human Hematopoietic Stem and Progenitor Cells – Abstract #734
Session: Targeted Genome Editing: Methods and Technology
Oral Presentation – Saturday, May 7, 2016
Hemoglobinopathies

Targeted Gene Addition in CD34+ Cells from Healthy Donors and Fanconi Anemia Patients – Abstract #558
Session: Targeted Genome Editing III
Poster Presentation – Friday, May 6, 2016
Cancer Immunotherapy

Single Chain TCR Gene Editing in Adoptive Cell Therapy for Multiple Myeloma – Abstract #752
Session: Cancer-Immunotherapy, Cancer Vaccines III
Oral Presentation – Saturday, May 7, 2016
Monogenic Diseases

Towards Clinical Translation of Hematopoietic Stem Cell Gene Editing for the Correction of SCID-X1 Mutations – Abstract #37
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

Correction of SCID-X1 by Targeted Genome Editing of Hematopoietic Stem/Progenitor Cells (HSPC) in the Mouse Model – Abstract #42
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

Technology Developments and other Applications

Highly Efficient Homology-Driven Genome Editing in Human T Cells with Combined Zinc-Finger Nuclease mRNA and AAV6 Donor Delivery and Improved Efficiency Under Serum-Free Conditions – Abstract #133
Session: Targeted Genome Editing I
Poster Presentation – Wednesday, May 4, 2016

Valproic Acid Treatment Enhances Hematopoietic Stem and Progenitor Cell Multipotency Ex Vivo for Enhanced Long-Term Engraftment of Gene-Modified Cells – Abstract #432
Session: Immunological Aspects of Gene Therapy I
Poster Presentation – Thursday, May 5, 2016

Highly Efficient, ZFN-Driven Knockout of Surface Expression of the T-Cell Receptor and HLA Class I Proteins in Human T-Cells for Enhancing Allogeneic Adoptive Cell Therapies – Abstract #641
Session: Cancer-Immunotherapy, Cancer Vaccines III
Poster Presentation – Friday, May 6, 2016

Enhanced FVIII AAV Vector Cassette Produces Improved Virus Yields and Supraphysiological FVIII Levels In Vivo – Abstract #684
Session: Hematologic & Immunologic Diseases II
Poster Presentation – Friday, May 6, 2016

Genome Editing of Inducible Cell Lines for Scalable Production of Improved Lentiviral Vectors for Human Gene Therapy – Abstract #286
Session: Vector and Cell Engineering/Manufacturing
Oral Presentation – Thursday, May 5, 2016

Characterization of Chromosomal Alterations Using a Zinc-Finger Nuclease Targeting Both the Beta- and Delta-Globin Gene Loci in Hematopoietic Stem/Progenitor cells – Abstract #118
Session: Targeted Genome Editing I
Poster Presentation – Wednesday, May 4, 2016

All abstracts for the ASGCT (Free ASGCT Whitepaper) meeting are available online at 2016 ASGCT (Free ASGCT Whitepaper) Annual Meeting Abstracts.