1stOncology™: Cancer Intelligence Service – Page 16487 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Mersana Therapeutics’ New Immunoconjugate Demonstrates Anti-Cancer Activity in Non-Small Cell Lung Cancer and Ovarian Cancer Tumor Models

On April 18, 2016 Mersana Therapeutics, Inc. reported that preclinical data for its new immunoconjugate product candidate, XMT-1536, demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models (Press release, Mersana Therapeutics, APR 18, 2016, View Source [SID:1234513852]). The data were presented today during a poster session at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin antibody-drug conjugate (ADC) platform. Dolaflexin is one of Mersana’s proprietary Fleximer immunoconjugate platforms.

"We are encouraged by the durable regressions XMT-1536 achieved in non-small cell lung cancer and ovarian cancer tumor models, as well as the excellent tolerability and pharmacokinetics in non-human primate exploratory toxicology studies," said Donald A. Bergstrom, MD, PhD, Chief Medical Officer of Mersana. "Based on these data, we are advancing XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors."

The study evaluated XMT-1536 in non-squamous NSCLC and non-mucinous ovarian cancer tumor models, indications in which NaPi2b is highly expressed. XMT-1536 demonstrated significant efficacy in all four patient-derived xenograft models representative of the target patient populations. In three patient-derived models of NSCLC, including KRAS-mutant NSCLC, XMT-1536 induced tumor regressions after three weekly doses of 3 mg/kg. In an ovarian cancer xenograft model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg, and complete tumor regressions after a single dose of 5 mg/kg or three weekly doses of 3 mg/kg. XMT-1536 was well-tolerated with no evidence of bone marrow toxicity in non-human primates at up to seven times the dose associated with tumor regression in the mouse xenograft models.

"XMT-1536 further validates the ability of Mersana’s Fleximer platform to generate targeted therapies that have the potential to address unmet needs and improve outcomes for patients with cancer. While there have been recent advancements in the treatment of non-small cell lung cancer and ovarian cancer, there remains tremendous need to address the significant proportion of patients who do not derive full benefit from currently available treatments," said Anna Protopapas, President and Chief Executive Officer of Mersana. "We look forward to the continued development of this second product candidate in our growing pipeline of Fleximer-based immunoconjugate therapies, as we prepare to enter the clinic with XMT-1522 this year."

New preclinical data further supporting the development of IPH4301 presented at the AACR meeting

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]).

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".

MB-102

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.

MB-101

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.

Innate Pharma presents new CD73 checkpoint inhibitor program

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.

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".