1stOncology™: Cancer Intelligence Service – Page 17137 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

First-in-class CD39 checkpoint inhibitor presented at the AACR meeting

On April 19, 2016 Innate Pharma and OREGA Biotech today presented preclinical data on IPH52, a new CD39 checkpoint inhibitor program, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 19, 2016, View Source [SID:1234511088]).

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!

Poster #3222 presents IPH52, Innate’s humanized anti-CD39 blocking antibody. This novel antibody exhibits high affinity and specificity for CD39 and potently inhibits ATPase activity in in vitro assays and ex vivo models with patient biopsies. In a murine tumor model, treatment with anti-CD39 antibody results in a significant decrease in tumor volume, and improved survival.

Poster #3218 presents for the first time the impact of CD39 disruption on the efficacy of other cancer therapeutics by comparing their effects in wildtype versus CD39 knock-out mice. The results revealed that CD39 deficiency sensitized to anti-PD1 treatment in animals that failed to respond to anti-PD-1 treatment. The antitumor efficacy of CD39 disruption is further improved when combined with an immunogenic chemotherapy. In animals bearing PD-1 insensitive tumors, combination of immunogenic chemotherapy, anti-PD1 antibody and CD39 disruption led to complete tumor eradication and long term protection (specific anti-tumor immunity) in most animals. The efficacy of an ADCC-inducing cytotoxic antibody was also improved in CD39 knock-out mice compared to wildtype.

Nicolai Wagtmann, CSO of Innate Pharma, said: "Taken together, the data presented by Innate and our partner OREGA Biotech form a very promising body of evidence supporting the development of this new, first-in-class checkpoint inhibitor antibody. The results presented today raise exciting perspectives for the development of IPH52, both as single-agent and in combination with other checkpoint inhibitors, and we are eager to now take this first-in-class candidate forward into the preclinical development phases".

Jeremy Bastid, COO of OREGA Biotech, further commented: "CD39 mediates immunosuppression through a different mechanism than other immune checkpoints and may broadly impede the efficacy of cancer therapies. The exciting data released today using both antibody blockade and genetic CD39 deficiency shed light on the capacity of CD39 disruption to drive antitumor immune responses, either alone or in combination with PD-1 checkpoint blockers, ADCC antibodies and immunogenic chemotherapy, suggesting broad development potential".

The cohesin-associated protein Wapal is required for proper Polycomb-mediated gene silencing.

The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcriptional regulation. The cohesin-associated protein Wapal plays a central role in off-loading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood. We used embryonic stem cells as a model, given that the well-defined transcriptional regulatory circuits were established through master transcription factors and epigenetic pathways that regulate their ability to maintain a pluripotent state.
RNAi-mediated depletion of Wapal causes a loss of pluripotency, phenocopying loss of core cohesin subunits. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), we determine that Wapal occupies genomic sites distal to genes in combination with CTCF and core cohesin subunits such as Rad21. Interestingly, genomic sites occupied by Wapal appear enriched for cohesin, implying that Wapal does not off-load cohesin at regions it occupies. Wapal depletion induces derepression of Polycomb group (PcG) target genes without altering total levels of Polycomb-mediated histone modifications, implying that PcG enzymatic activity is preserved. By integrating ChIP-seq and gene expression changes data, we identify that Wapal binding is enriched at the promoters of PcG-silenced genes and is required for proper Polycomb repressive complex 2 (PRC2) recruitment. Lastly, we demonstrate that Wapal is required for the interaction of a distal cis-regulatory element (CRE) with the c-Fos promoter.
Collectively, this work indicates that Wapal plays a critical role in silencing of PcG target genes through the interaction of distal CREs with promoters.

Enhancement of Fluorescent Probe Penetration into Tumors In Vivo Using Unseeded Inertial Cavitation.

Ultrasound-induced cavitation has found many applications in the field of cancer therapy. One of its beneficial effects is the enhancement of drug intake by tumor cells. Our group has developed a device that can create and control unseeded cavitation in tissue using ultrasound. We conducted experiments on tumor-bearing mice using our device to assess the impact of sonication on the penetration of fluorescent probes into tumor cells. We studied the influence of pressure level, timing of sonication and sonication duration on treatment efficiency. Our results indicate that fluorescent probes penetrate better into tumors exposed to ultrasound. The best results revealed an increase in penetration of 61% and were obtained when sonicating the tumor in presence of the probes with a peak negative pressure at focus of 19 MPa. At this pressure level, the treatment generated only minor skin damage. Treatments could be significantly accelerated as equivalent enhanced penetration of probes was achieved when multiplying the initial raster scan speed by a factor of four.
Copyright © 2016 World Federation for Ultrasound in Medicine &amp; Biology. Published by Elsevier Inc. All rights reserved.

Recent advances in the development of new auristatins: structural modifications and application in antibody drug conjugates.

Dolastatin 10 is a powerful antineoplastic agent and microtubule inhibitor that was discovered by Pettit et al. and published in 1987. Since then, many research groups have engaged in SAR studies of synthetic analogues, termed &quot;auristatins&quot;. It was eventually discovered that auristatins are of great value as payloads in antibody drug conjugates (ADCs), which led to the FDA-approved ADC brentuximab vedotin (Seattle Genetics). Currently, over 30 ADCs in clinical trials employ auristatins as payloads, and there is a great interest in the research community, both on academic and industrial sides, to further study these analogues. This review will provide an overview of the recent advancements in auristatin development spanning a time frame of about the past ten years. The main focus will be to describe structural changes made to the auristatin peptide and their resulting biological activities in tumor cell proliferation assays. Selected ADC examples will also be described.

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody-Drug Conjugate.

The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody-drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics.