Member Info for Fadec92

Keytruda is a PD-1 not a ligand 1!

So that’s Mercks (Pembrolizumab) a PD-L1 Program Death Checkpoint Inhibitor, commercial name Keytruda!

BMS Bristol-Myers CTLA-4 Monoclonal Antibody (Ipilimumab) commercial name Yervoy!

Patent SDC-1802

Primary and Acquired resistance

In the foregoing embodiments, the drug to which the cancer has developed resistance is typically one which does not make use of inhibition of TYK2 kinase as its primary anticancer effect. More particularly, the drug is one which has an I C50 of greater than 20µ? against TYK2 kinase in a kinase inhibition assay, and more usually greater than 50 µ? (for example in the range 50-500µ?. In one embodiment, the drug to which the cancer has developed resistance is substantially inactive against TYK2 kinase.

The compounds of the invention can also be used for the treatment of a cancer in a patient who has not previously received chemotherapy for the treatment of that cancer, and wherein the cancer is known to be resistant to one or more anti-cancer drugs.

In each of the foregoing embodiments 2.52 to 2.63, the drug-resistant cancer can be selected from categories A to H below and any one or more individual combinations of drugs and cancers disclosed therein:

H. Cells that have shown intrinsic or acquired resistance to other small-molecule or monoclonal antibody cancer therapies such as:

Vorinostat, Abiraterone, Venetodax, Trastuzumab, Bevacizumab, Rituximab,(Ipilimumab, Pembrolizumab), nivolumab.

Primary and Adaptive Resistance to Immunotherapy

Patients who have primary resistance to checkpoint inhibitors do not respond to the initial therapy. Ongoing studies indicate that both tumor-cell-intrinsic and tumor-cell-extrinsic factors contribute to the resistance mechanisms (Table 2).

The most straightforward reason why a tumor would not respond to immune checkpoint therapy or ACT is lack of recognition by T cells because of absence of tumor antigens. Alternatively, cancer cells may have tumor antigens but develop mechanisms to avoid presenting them on the surface restricted by MHC, due to alterations in the antigen-presenting machinery, beta-2-microglobulin (B2M), or MHC itself. B2M is required for HLA class I folding and transport to the cell surface, and its genetic deficiency leads to lack of CD8 T cell recognition.

One mechanism by which cancer cells could escape the effects of interferon gamma is by downregulating or mutating molecules involved in the interferon gamma signaling pathway, which goes through the interferon gamma receptor chains JAK1 and/or JAK2 and the signal transducer and activators of transcription (STATs). In cell line and animal models, mutations or epigenetic silencing of molecules in the interferon receptor signaling pathway results in loss of the antitumor effects of interferon gamma. Analysis of tumors in patients who did not respond to therapy with the anti-CTLA-4 antibody ipilimumab revealed an enriched frequency of mutations in the interferon gamma pathway genes interferon gamma receptor 1 and 2 (IFNGR1 and IFNGR2), JAK2, and interferon regulatory factor 1 (IRF1).

Any of these mutations would prevent signaling in response to interferon gamma and give an advantage to the tumor cells escaping from T cells, thereby resulting in primary resistance to anti-CTLA-4 therapy. Mutations in this pathway would additionally result in lack of PD-L1 expression upon interferon gamma exposure, thereby resulting in cancer cells that would be genetically negative for inducible PD-L1 expression. In such a scenario, blocking PD-L1 or PD-1 with therapeutic antibodies would not be useful, and these would be patients who are primary resistant to anti-PD-1 therapy.

https://www.cell.com/cell/pdf/S0092-8674(17)30065-X.pdf

JAK Mutations as Escape Mechanisms to Anti–PD-1 Therapy

However, the majority of patients with melanoma do not respond to anti–PD-1 monotherapy, including some patients with high levels of PD-L1 expression and CD8+ T-cell infiltrates in their tumor. Moreover, although tumor responses upon anti–PD-1 therapy are long lasting, some patients can eventually relapse from their disease. The mechanisms behind these primary and secondary refractory diseases to anti–PD-1 therapy remain mostly unknown.

The team of Antoni Ribas and colleagues has recently shown that an escape mechanism found in secondary refractory disease can be attributed to mutations of genes involved in the IFN? pathway, either via loss-of-function mutations in the genes encoding for JAK1 and JAK2 (with concurrent deletion of the wild-type allele) or via truncating mutations of the MHC-I sub-unit beta-2-microglobulin (B2M; ref. 4).

In this issue of Cancer Discovery, the same team reports that loss-of-function JAK mutations can also be found in patients with primary resistance to anti–PD-1 therapy.

Inactivating JAK1 and JAK2 mutations might in theory impair the downstream signaling of IFN? receptors and therefore the ability of IFN? to induce a cell-cycle arrest of tumor cells and to upregulate PD-L1 and MHC-I expression on their outer membrane.

“These results are significant because they suggest that JAK mutations could be used as a genetic biomarker to identify patients who might not benefit from an anti–PD-1/PD-L1 therapy.”

https://cancerdiscovery.aacrjournals.org/content/7/2/128

Belhus on US 16/351620 there’s no hearings as such Sareum has provided the information on why the molecule should be classed as a new patent and not part of the older patent, and the answer is very reasonable they did not expect the results, the molecule is part of a collection of a group of molecules under FLT3 and is covered but dosnt provide any test data for it as it was not considered to be a lead molecule and this encompasses the argument why it should be classed separately!

John has provided a professional statement/deceleration and in-depth reason why, this is why I love patents because it shows the true value of something and not just opinions on what’s going on, time lines on such was they were granted a 2month extension and they provided all the necessary documentation for assessment on the 29th Oct 2019, so that’s why I thought there would be a answer just after Christmas but this could be that they had 2 months to provide the reasonable data to support the patent and is still under examination so it could be anyone’s guess as there’s not enough info to predict when!

Google’s good Utah!

https://en.m.wikipedia.org/wiki/IC50

Thanks Krone!

Pfizer JAK1/TYK2 which the JAK1 is slightly more selective than TYK2, here’s the Pharmacological profile!

Pfizer PF-06700841

IC50(JAK1) = 17 nM
IC50(TYK2) = 23 nM
IC50(JAK2)= 77 nM
JAK3 (IC50 = 6494 nM) or (6.49 µM)

SRA737 was said to be best in class and turned out to be right with two major companies discontinuing their CHK1’s!

It’s irrelevant as in SRA737 is only in class apart from a private company mentioned CHK1 by quote data, and SDC-1802 is the only Tyk2 biased/Selective TYK2/JAK1 inhibitor in Solid Tumors, not in B-Cell Lymphomas as Nimbus has a Tyk2, maybe best in class for SDC-1801 but will probably have to put in a full shift in with the BMS/Nimbus Very selective TYK2’s with all the good things being said by them!

DNA damage ie SRA737 is a totally different mechanism to Immunotherapy, so immune checkpoint inhibitors has no relevance to a CHK1 Inhibitor, it’s totally different CHK1 is common too PARPS, ATM, ATR and Wee1 in that it stops Cancer repairing itself by breaking stopping stands on DNA!

Immune Checkpoint inhibitors use the body’s immune system to target cancer, PD-L1 and CTLA-4 are two kinds, TYK2/JAK1 is more closer to Immunotherapy as inhibits signals between Cancer and Immune System/Inflammation!

Dropping again hope they have something up their sleeve to improve things!

RMM? It’s Plusone on Stocktwits!

Don it’s not to do with NK Cells!

It’s a protein that is upregulated MHC-I expression and is a marker for immune checkpoint resistance,it normally help immune cells to recognise and attack cancer cells. When the genes fail to function as normal, the immune system is unable to spot cancer cells!

MHC class I-related protein, MR1

JAK Mutations as Escape Mechanisms to Anti–PD-1 Therapy

However, the majority of patients with melanoma do not respond to anti–PD-1 monotherapy, including some patients with high levels of PD-L1 expression and CD8+ T-cell infiltrates in their tumor. Moreover, although tumor responses upon anti–PD-1 therapy are long lasting, some patients can eventually relapse from their disease. The mechanisms behind these primary and secondary refractory diseases to anti–PD-1 therapy remain mostly unknown.

The team of Antoni Ribas and colleagues has recently shown that an escape mechanism found in secondary refractory disease can be attributed to mutations of genes involved in the IFN? pathway, either via loss-of-function mutations in the genes encoding for JAK1 and JAK2 (with concurrent deletion of the wild-type allele) or via truncating mutations of the MHC-I sub-unit beta-2-microglobulin (B2M; ref. 4).

In this issue of Cancer Discovery, the same team reports that loss-of-function JAK mutations can also be found in patients with primary resistance to anti–PD-1 therapy.

Inactivating JAK1 and JAK2 mutations might in theory impair the downstream signaling of IFN? receptors and therefore the ability of IFN? to induce a cell-cycle arrest of tumor cells and to upregulate PD-L1 and MHC-I expression on their outer membrane (Fig. 1B).

“These results are significant because they suggest that JAK mutations could be used as a genetic biomarker to identify patients who might not benefit from an anti–PD-1/PD-L1 therapy.”

https://cancerdiscovery.aacrjournals.org/content/7/2/128

https://cancerdiscovery.aacrjournals.org/content/candisc/7/2/128/F1.large.jpg?download=true

https://twitter.com/fadec92/status/1220017471853219841?s=21

Thanks ICR A good little mention of JAKS and the new HLA In the news as recently and discussed on this forum, I’ve created a picture of the interactions!

The human MHC is also called the HLA complex (Major histocompatibility complex)

https://imgur.com/a/rMAErW5

The study is published in Nature Communications today (Thursday), and was funded by Cancer Research UK and the Schottlander Research Charitable Trust. It is part of a programme of work at The Institute of Cancer Research (ICR) to understand how cancers adapt and evolve in response to changes in their environment, such as by evading the immune system or becoming resistant to treatment

https://www.icr.ac.uk/news-archive/cancers-engaged-in-evolutionary-arms-race-with-immune-system

Cancers engaged in evolutionary arms race with immune system

Mutations to evade immune attack

Importantly, the two stomach and gullet tumours with the highest level of infiltration from immune cells had each developed several mutations that allowed them to evade immune attack.

These mutations occurred in genes called B2M, HLA and JAK1/2, which normally help immune cells to recognise and attack cancer cells. When the genes fail to function as normal, the immune system is unable to spot cancer cells despite their large numbers of mutations.

The researchers believe that highly mutated cancers come under particularly strong selective pressure from the immune system and can draw on huge genetic variation to evolve more rapidly than other cancers, making them particularly hard to treat.

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

https://www.nature.com/articles/s41467-019-13915-7

http://investor.sierraoncology.com/2020-01-22-Sierra-Oncology-Announces-Reverse-Stock-Split

http://orcid.org/0000-0003-3194-3135

Have a look, here is Andrew Sewell’s ORCID identifier!

This HLA is the Adaptive Immune system!

I wouldn’t agree as worrying the main thing is better armory to kill Cancer with potential beating therapy’s, I don’t think there will be a one all way of beating Cancer as it always evolves and mutates and then scientists have to find the next way to beat it, ie like immune checkpoint blockage resistance, Hopefully it will work and perform in the clinical setting, but will be a tool to use against Cancer rather than a cure!

https://en.m.wikipedia.org/wiki/Human_leukocyte_antigen

https://www.nature.com/articles/s41590-019-0578-8

Gilead has already made an agreement with SRRA!

"Asset Purchase Agreement with Gilead Sciences, Inc. for momelotinib upon Sierra closing a qualified financing"

Financing already in place, no mention at all for milestone as SRRA seaking non-dillutive funding which SRA737 dosn't seam SRRA's focus, or its all one big game for a reduced payment and has been the same stance since last august dont think so or Sareum and ICR having none of it, hope something positive comes out of this from Sareum and ICR because in combination looks impressive with the results from the MD Anderson clinic with T.Sen in SCLC with Gembcitabine and Permbrozilumab!