On April 19, 2016 – Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported new preclinical data demonstrating enhanced systemic anti-tumor activity in preclinical cancer models with intra-tumoral administration of IMO-2125 in combination with an inhibitor of the immunosuppressive enzyme, indoleamine-pyrrole 2,3-dioxygenase (IDO1) (Press release, Idera Pharmaceuticals, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158201 [SID:1234511058]). IMO-2125 is a synthetic oligonucleotide-based agonist of Toll-like receptor 9 discovered and developed by Idera. IDO is one of several immune checkpoints involved in tumor immune escape. IDO-1 inhibitors are currently in clinical development. These data are being presented at the AACR (Free AACR Whitepaper) Annual Meeting 2016 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!

"There is an extensive body of evidence which demonstrates that modulating the tumor microenvironment is critical to a successful outcome in cancer immunotherapy", stated Sudhir Agrawal, D.Phil., President of Research at Idera Pharmaceuticals. "In preclinical models, previously we have seen compelling systemic anti-tumor effects with intra-tumoral IMO-2125 monotherapy, in combination with inhibitors of CTLA-4, PD-1, and now, IDO."

In the presentation, entitled "Creating the tumor microenvironment for effective immunotherapy: Anti-tumor activity of intra-tumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO)," Idera scientists presented data further supporting the hypothesis that intra-tumoral IMO-2125 changes the tumor microenvironment by increasing tumor-infiltrating lymphocytes (TILs) and generating a favorable tumor microenvironment. Changes in IDO checkpoint inhibitor expression were also observed.

In the current studies, IMO-2125 (alone and in combination with an IDO-1 inhibitor) increased TIL infiltration and decreased the growth of treated and distant tumors, providing evidence of an enhanced systemic antitumor immune response compared to either agent given alone.

In the study we evaluated the antitumor activity of i.t. IMO-2125 in combination with an IDO1 inhibitor in a murine syngeneic colon carcinoma CT26 model. There was a statistically significant decrease in the growth of both local and distant tumors which was greater for combination therapy than for either IMO-2125 or IDO-1 alone (for lung metastases: combination vs IMO-2125: P = 0.0393; combination vs IDO-1 inhibitor: P = 0.0128).

These results and previous observations with IMO plus anti-CTLA4 and IMO plus PD-1 demonstrate that combination immunotherapy with IMO-2125 has the potential to improve clinical outcomes over currently available anti-CTLA4 and PD-1 inhibitors, and now IDO-1 inhibitors. These presentations are all currently available on Idera’s website at View Source

In partnership with the MD Anderson Cancer Center, the company is currently conducting a Phase 1/2 clinical trial of intra-tumoral IMO-2125 in combination with ipilimumab (CTLA4) for the treatment of pembrolizumab (PD1) treated refractory metastatic melanoma patients. The study has also recently been amended to include an arm studying the combination of IMO-2125 and PD1 in the same patient population.

About Toll-like Receptors and Idera’s Immuno-Oncology Research Program

Toll-like receptors (TLRs) are key components of the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) and, more recently, IDO inhibitors work by targeting mechanisms of adaptive immune resistance. It is believed that intra-tumoral administration of IMO-2125 may potentiate the activity of all of these immunotherapies by creating a more favorable tumor microenvironment that includes increased infiltration by TILs.

Idera’s TLR9 agonist, IMO-2125 has been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown to activate dendritic cells and induce interferon and other cytokines. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In preclinical studies in cancer models, IMO-2125 has shown dose-dependent anti-tumor activity in the injected tumor as well as in distant tumors. Anti-tumor activity is associated with changes in the tumor microenvironment, increased T-cell infiltration, and induction of durable, tumor specific memory. In combination with anti-CTLA4, anti-PD1, and IDO1 inhibitor, IMO-2125 has shown greater anti-tumor activity than with either agent alone. In previously completed clinical trials, subcutaneous administration of IMO-2125 was generally well tolerated in about 80 patients with hepatitis C.

There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC(50) values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues.
Copyright © 2014 John Wiley & Sons, Ltd.

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!

Twenty-two patients with pathologically confirmed glioblastoma who had received concurrent CCRT with TMZ underwent conventional MRI including T1-weighted imaging(T1WI), T2-weighted imaging(T2WI), fluid attenuated inversion recovery(FLAIR)and contrast-enhanced T1WI(T1Ce). Five GLCM texture maps of contrast, energy, entropy, correlation and homogeneity were generated for each MRI series. Of the aforementioned 5 texture features, the most significant features were contrast and correlation on T2WI with areas under ROC curve of 0.883 and 0.892, respectively, and they had the same sensitivity of 75%, specificity of 100%, accuracy of 86.4%, PPV of 100% and NPV of 76.9% in differentiation true progression from pseudoprogression.
Copyright © 2015. Published by Elsevier Inc.

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!

On April 19, 2016 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported the presentation of preclinical data from five programs at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, MacroGenics, APR 19, 2016, View Source [SID:1234511059]). Four of the five presented posters were from studies based on MacroGenics’ Dual-Affinity Re-Targeting, or DART, bispecific technology. MacroGenics also presented data from its preclinical anti-B7-H3 antibody-drug conjugate program within the company’s B7-H3 franchise.

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!

"MacroGenics is encouraged by the promising preclinical data from these five programs," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "With a focus on developing innovative medicines for patients in need, our company is bolstered by early-stage, positive preliminary data from these programs targeting various cancers. With eight molecules in clinical development across immuno-oncology and autoimmune disorders today and plans to expand into infectious diseases, the MacroGenics team is making progress towards our mission of bringing new breakthrough treatments to patients suffering from a range of diseases."

MacroGenics AACR (Free AACR Whitepaper) 2016 Poster Presentations

Each of MacroGenics’ poster presentations described below may be accessed under "Events & Presentations" in the Investors section of the company’s website at View Source

B7-H3 Franchise: As previously reported, MacroGenics is developing a portfolio of therapeutics that target B7-H3, a member of the B7 family of molecules involved in immune regulation, through complementary mechanisms of action that also take advantage of the antigen’s broad expression across multiple solid tumor types. In the presentation titled "Anti-B7-H3 antibody-drug conjugates as potential therapeutics for solid cancer," MacroGenics evaluated the therapeutic potential of anti-B7-H3 antibody-drug conjugates (ADCs) in multiple in vitro and in vivo tumor cell line cases representing human cancer types that overexpress B7-H3. Several anti-B7-H3 ADCs exhibited specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro and in vivo, including breast, lung, ovarian, pancreatic, and prostate cancer lines as well as melanoma. The study results show the potential of B7-H3-targeted ADCs for the treatment of solid cancers that express B7-H3.

MGD013: MGD013, a compound developed using MacroGenics’ DART platform, is a single agent designed to block PD-1 and LAG-3, two immune checkpoint molecules that are co-expressed on T cells. Published work in nonclinical models has shown that combining LAG-3 blockade with PD-1 checkpoint inhibition can further boost the anti-tumor response observed with anti-PD-1 alone. In the presentation titled "MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART) protein with T-cell immunomodulatory activity for cancer treatment," MacroGenics demonstrated that MGD013 has the potential to promote anti-tumor activity by simultaneously blocking both PD-1 and LAG-3. In the study, monoclonal antibodies (mAbs) against PD-1 and LAG-3 were engineered into MGD013, an Fc-bearing DART molecule. MGD013 was shown to block PD-1/PD-L1, PD-1/PD-L2 and LAG-3/MHC-II interactions to levels comparable to those observed with its independent constituents. Furthermore, MGD013 enhanced T-cell response (upon antigen re-challenge), as measured by cytokine secretion, to an extent greater extent than that observed with the independent blockade of each pathway or even when both pathways were inhibited with a combination of anti-PD-1 and anti-LAG-3 mAbs. The results of the study helped support further clinical development of MGD013. MacroGenics plans to submit an Investigational New Drug (IND) application for MGD013 in 2017.

ROR1 x CD3 DART: The receptor tyrosine kinase-like orphan receptor 1, ROR1, is overexpressed in chronic lymphocytic leukemia and a subset of solid tumors, including lung, breast, ovarian, colon, sarcoma and pancreatic cancers. In the presentation titled "Development of a humanized ROR1 x CD3 bispecific DART molecule for the treatment of solid and liquid tumors," MacroGenics demonstrated that a ROR1 x CD3 DART molecule was able to kill ROR1-expressing target cells in vitro. T-cell activation and cytokine release was strictly mediated upon target antigen engagement and not observed with leukocytes alone. The DART molecule also demonstrated anti-tumor activity in vivo, with high response rates in several mouse tumor xenograft models. The promising in vitro and in vivo study results support continued research on the use of ROR1 x CD3 DART molecules as a potential treatment option for cancer patients.

IL13Rα2 x CD3 DART: IL13Rα2 is a membrane-bound protein that has been found to be expressed in malignant tumors. "Development of an IL13Ralpha2 x CD3 bispecific DART protein for redirected T-cell killing of solid tumors" introduced the IL13Rα2 x CD3 DART molecule that re-targets cytotoxic T cells through its CD3 arm to IL13Rα2 on tumors cells, resulting in the killing of tumor cells. After selection from a range of IL13Rα2 x CD3 DART prototypes, a lead candidate was selected and converted into a humanized, Fc-bearing DART molecule that mediated potent redirected T-cell killing of tumor cells. The study further showed that administration of the Fc-bearing IL13Rα2 x CD3 DART molecule mediated potent anti-tumor activity in vivo in mice reconstituted with human immune cells. Further studies are underway to characterize the molecule as a potential development candidate for the treatment of IL13Rα2-positive cancers.

EphA2 x CD3 DART: MacroGenics has selected EphA2, a receptor tyrosine kinase that plays a critical role in cancer progression, as a potential therapeutic target for a new DART molecule designed to co-engage cytotoxic T cells (via their CD3 component) with EphA2-expressing tumor cells. In the presentation titled "Evaluation of EphA2 as a therapeutic target for redirected T-cell killing by DART bispecific molecules," MacroGenics researchers identified seven anti-EphA2 mAbs recognizing independent epitopes that were engineered into EphA2 x CD3 DART molecules showing a range of potency in redirecting T cells to kill EphA2-expressing target cells. A lead EphA2 x CD3 DART molecule was selected based on potency, engineered into an Fc-bearing DART molecule and shown to mediate target dependent anti-tumor activity in vitro and in vivo. MacroGenics has been encouraged by the results of this study and believes further preclinical assessment studies of EphA2 x CD3 DART molecules are warranted.
Background on DART Platform

MacroGenics’ DART platform enables the targeting of multiple antigens or cells by using a single molecule with an antibody-like structure. DART molecules can be configured for the potential treatment of cancer, autoimmune disorders and infectious diseases. These DART molecules can be tailored for either short or prolonged pharmacokinetics and have demonstrated good stability and attractive manufacturability. Six DART molecules, including programs being developed by MacroGenics and its collaborators, are currently being evaluated in Phase 1 clinical studies.

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.

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!