On April 8, 2022 Shattuck Labs, Inc. (Shattuck) (NASDAQ: STTK), a clinical-stage biotechnology company pioneering the development of bi-functional fusion proteins as a new class of biologic medicine for the treatment of patients with cancer and autoimmune disease, reported preclinical data at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Shattuck Labs, APR 8, 2022, View Source [SID1234611834]). This includes data from SL-9258 (TIGIT-Fc-LIGHT), derived from the company’s ARC platform, and the company’s GADLEN platform.

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"We have made excellent progress advancing compounds in our preclinical pipeline," said Taylor Schreiber, M.D., Ph.D., Chief Executive Officer of Shattuck. "Data from our SL-9258 compound indicate potent modulation of myeloid cells, T cells, and cytokines, including IL-2, which collectively translated to superior anti-tumor activity in comparison to TIGIT and PD-L1 antibodies in a preclinical model of PD-1 acquired resistance. In addition, multiple compounds from our gamma delta T cell engager, or GADLEN, platform have shown specific anti-tumor activity in preclinical studies, which will help guide our lead candidate selection and clinical development strategy. We look forward to nominating our next clinical product candidate in 2022."

Details of the presentations are as follows:

Abstract title: LIGHT (TNFSF14) costimulation with TIGIT blockade broadens the activity of checkpoint inhibitors (CPIs) into checkpoint inhibitor refractory and resistant tumors through targeted myeloid cell and effector lymphocyte activation

Shattuck presented preclinical data for SL-9258 (TIGIT-Fc-LIGHT), a bispecific fusion protein from its ARC platform, demonstrating that SL-9258 simultaneously provides checkpoint blockade to all tumor-expressed PVR ligands and broadens immune costimulation by the TNF ligand known as LIGHT. LIGHT’s ability to bind and activate CD8+ T and natural killer cells through interactions with one of its receptors known as HVEM and myeloid cells through interactions with its other receptor known as LTbR, translates into strong anti-tumor responses in checkpoint primary and acquired resistance murine tumor models, where TIGIT blocking antibodies demonstrate no activity.

TIGIT-Fc-LIGHT was evaluated and well tolerated in non-human primates at doses up to 40 mg/kg and similar on-target pharmacodynamic activity was observed to what was characterized preclinically in mice. Together, these results suggest that TIGIT-Fc-LIGHT may provide clinical benefit to patients that are refractory to conventional checkpoint blockade therapy.

Abstract title: Bispecific gamma/delta T cell engagers containing butyrophilin 2A1/3A1 heterodimeric fusion protein efficiently activate Vg9Vd2+ T cells and promote tumor cell killing

Shattuck presented preclinical data highlighting the potential of GADLENs to direct gamma delta T cells to kill tumor cells and in the process, further elucidate tumor cell markers which are important for the therapeutic activity of gamma delta T cell-based therapies.

Shattuck’s bispecific GADLENs containing heterodimeric BTN2A1 and BTN3A1 extracellular domains fused via inert Fc linkers to scFv domains, targeting CD19 or CD20 tumor-antigens, demonstrated an ability to induce proliferation, degranulation, and cytokine production in Vg9Vd2+ T cells with costimulation of a natural cytotoxicity receptor or T cell costimulatory receptor. Further, CD19 and CD20 directed GADLENs enhanced the specific killing of lymphoma cells that express both antigen targets.

Additional meeting information can be found on the AACR (Free AACR Whitepaper) website, View Source The posters will be available under Posters on the Company’s website shortly after the event.

On April 8, 2022 Redx (AIM: REDX), the clinical-stage biotechnology company focused on discovering and developing novel, small molecule, highly targeted therapeutics for the treatment of cancer and fibrotic disease, reported that its poster at theAmerican Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (8-13 April,New Orleans) will be available for viewing from today (Press release, Redx Pharma, APR 8, 2022, View Source [SID1234611833]). A formal presentation of the poster by the authors will be made at the conference on 12 April.

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RXC004, a highly potent and selective, orally active once-daily Porcupine inhibitor, is being developed as a targeted therapy for Wnt-ligand driven cancer. It is currently being evaluated as monotherapy in Phase 2 proof-of-concept clinical trials in genetically selected patients with pancreatic cancer and metastatic colorectal cancer and in unselected patients with biliary cancer. Additionally, RXC004 is in a Phase 1 combination study with nivolumab, an anti-PD-1 antibody from which a dose for the combination arm of the Phase will be selected this year. Data readouts from the Phase 2 studies are expected in 2023.

The poster presented at the AACR (Free AACR Whitepaper) meeting and entitled ‘Pre-clinical efficacy of the Wnt pathway inhibitor RXC004 in combination with anti-cancer therapies’ describes preclinical data which demonstrate that RXC004 in combination with clinically relevant standard of care chemotherapy regimens could lead to potential benefit, including survival, over chemotherapy alone. The poster hypothesised that the RXC004-induced downregulation of DNA repair pathway genes observed in vitro could contribute to the beneficial effect seen in combination with a PARP inhibitor in vitro as well as the combination effect observedin vivo with the standard of care chemotherapy agents.

D r Jane Robertson, Chief Medical Officer, Redx Pharma, said: "This preclinical data further underpins our excitement around the therapeutic potential of RXC004, and the role of effective Wnt pathway blockade, in tackling a number of difficult to treat cancers with high unmet need."

More information on the contents of the poster The presented poster, is available on the AACR (Free AACR Whitepaper) e-poster website and the investor section of the Company’s website at: View Source It describes how RXC004 was evaluated in a mouse colorectal xenograft model alone and in combination with both the FOLFIRI

* and FOLFIRINOX
** treatment regimens, currently both standard of care chemotherapy in colorectal cancer. Efficacy was measured by tumour volume and survival endpoint. In addition, RXC004 was studied in vitro, as monotherapy and in combination with a PARP inhibitor in genetically selected cell lines with both RSPO-fusion and RNF43 mutation. Combination and monotherapy effects on proliferation and effects on downstream signalling were investigated.

About RXC004
RXC004, a highly potent and selective, orally active once-daily Porcupine inhibitor is being developed as a targeted therapy for Wnt-ligand driven cancer. Aberrant Wnt signalling contributes directly to tumour growth and plays an important role in immune evasion, which has also been linked to resistance to immune-checkpoint inhibitors (ICIs) such as nivolumab. RXC004 has the potential to both directly inhibit the tumour growth and have an immune-enhancing effect in patients with tumours that have high Wnt-ligand dependency, such as tumours with mutations in the RNF43 gene and fusions in the RSPO gene family.

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 antibodies have revolutionised the treatment of cancer, but do not work in all patients. Wnt pathway activation can enhance the ability of the tumour to evade destruction by the immune system and has been linked to lack of response to ICIs in these tumours. Our scientists have demonstrated preclinically that RXC004 can block activation of the Wnt pathway and restore the ability of the immune system to fight the tumour. Thus, RXC004 offers potential as a monotherapy or combination therapy.

On April 8, 2022 Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) ("Corbus" or the "Company"), an immunology company, reported the first preclinical data for CRB-601 are being presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held from April 8-13, 2022, in New Orleans, LA (Press release, Corbus Pharmaceuticals , APR 8, 2022, View Source [SID1234611799]). CRB-601 is a potent and selective αvb8 integrin monoclonal antibody designed to block the activation of TGFb in the local tumor microenvironment. TGFb is thought to be the only ligand of the αvb8 integrin. Inhibiting its ability to bind to αvb8 could therefore play an important role in the regulation of this pleiotropic cytokine. The in vitro preclinical data presented demonstrate the high affinity of CRB-601 for αvb8 and the resulting effect on TGFb. The data also show significant inhibition of tumor growth in a syngeneic model of colon cancer (MC38) by CRB-601, both as a single agent and in combination with anti PD-1 treatment. These effects are supported by the coincident increase in CD8-positive T cells in the tumor microenvironment.

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"The increase of tumor infiltration by T-cells stimulated by CRB-601 is quite exciting. The effects of CRB-601 are consistent with the proposed mechanism of blocking TGFb activation, which can potentially enable an anti-tumor immune response and be an effective adjunct to immune checkpoint therapies. We are excited to bring this mechanism of action to the clinic and define the potential benefit it could bring to patients," commented Rachael Brake, Ph.D., Chief Scientific Officer of Corbus.

Corbus is currently developing CRB-601 as a potential treatment for solid tumor cancers, and the program is advancing toward an IND submission in the first half of 2023.

The AACR (Free AACR Whitepaper) poster is available on the Company’s website at: www.corbuspharma.com/AACRposter

Additionally, Corbus has published an updated Corporate Presentation providing an overview of the Company’s full portfolio on its website at: ir.corbuspharma.com/presentations

On April 8, 2022 Iterion Therapeutics, Inc., a venture-backed, clinical-stage biotechnology company developing novel cancer therapeutics, reported that three posters involving research into tegavivint will be presented at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, including initial results from a Phase 1 study of tegavivint in patients with desmoid sarcomas (Press release, Iterion Therapeutics, APR 8, 2022, View Source [SID1234611796]). AACR (Free AACR Whitepaper) 2022 is being held April 8-13, 2022, in New Orleans.

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Tegavivint is a potent and selective first-in-class small molecule inhibitor of Transducin Beta-like Protein One (TBL1), a novel downstream co-factor in the Wnt/beta-catenin signaling pathway. Increased expression beta-catenin and TBL1 are associated with metastasis and poor prognosis in a broad range of tumor types. Tegavivint’s targeting of TBL1 prevents TBL1/beta-catenin complex formation, specifically inhibiting beta-catenin’s oncogenic transcriptional activity without disrupting key cell membrane functions that have been linked to toxicity common to other drugs in this pathway.

The first poster, titled, "A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors," will be presented on Tuesday, April 12, 2022, at 9:00 a.m., CDT, during the Phase I Clinical Trials 2 session (poster board number 10; abstract number CT185). The poster details results from the dose-escalation portion of a Phase 1 trial of tegavivint in adult patients with progressive, unresectable desmoid sarcoma. The primary objective of the study was to evaluate the safety and tolerability of tegavivint administered once weekly and to determine a recommended phase 2 dose (RP2D). As described in the poster, tegavivint was well tolerated with grade 3 treatment related adverse events (TRAEs) reported in four patients for hypophosphatemia, stomatitis, headache, and elevated ALT; no grade 4 or 5 TRAEs were observed. No dose-limiting toxicities (DLT) were observed, and the maximum tolerated dose (MTD) was not declared. Objective responses (WHO and RECIST) were observed at multiple dose levels and the clinical benefit rate was 82% (n = 14). The RP2D was declared based on lack of DLTs, pharmacologically relevant plasma concentrations, and preliminary efficacy. In conclusion, tegavivint’s preliminary efficacy and favorable safety profile supported continued development through a dose expansion arm of the study, data from which will be presented at a future conference.

"We are very excited to report research describing tegavivint’s unique properties and therapeutic potential in multiple poster presentations at AACR (Free AACR Whitepaper) 2022; particularly the results of our first-in-man Phase 1 clinical study," said Rahul Aras, PhD, CEO of Iterion. "Taken together, these results demonstrate inhibition of TBL1 as a clinically viable strategy to curtail nuclear beta-catenin oncogenic activity in multiple cancer indications."

Dr. Aras continued, "Importantly, results from the dose-escalation part of the Phase 1 study of tegavivint in patients with progressive desmoid sarcomas demonstrated the drug to be well-tolerated and indicated clinical activity in this difficult-to-treat disease. While regarded as a high value oncology target, nuclear beta-catenin has historically been considered undruggable through conventional drug development. Upstream approaches targeting the Wnt/beta-catenin pathway have not clinically advanced, typically because of toxicity in early phase clinical development. However, we believe tegavivint’s ability to selectively disrupt the interaction of beta-catenin and TBL1 results in the specific degradation of nuclear beta-catenin without impacting key cell membrane functions that have been linked to previously reported toxicity. The Phase 1 data presented at AACR (Free AACR Whitepaper) 2022 demonstrate this capability, which we are now further investigating in three separate, ongoing clinical trials of tegavivint in AML, non-small cell lung cancer, and pediatric solid tumors."

The second poster, titled, "Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma," will be presented virtually by Kengo Nakahata, MD, PhD, Postdoctoral Associate, Texas Children’s Hospital on Friday, April 8, 2022, at 12:00 p.m., CDT. The poster reports results from a pre-clinical study examining the influence of tegavivint on the osteosarcoma (OS) tumor immune microenvironment and potential combination with anti-PD1 antibody therapy. Data from the study indicated that tegavivint as a monotherapy significantly suppressed the growth of murine OS tumors (p<0.05), while anti-PD1 monotherapy did not show any significant anti-tumor activity. Combining anti-PD1 with tegavivint was able to further improve overall anti-tumor activity. Tegavivint treatment was also associated with an intratumoral increase in CD8-positive T-cells and NK cells compared with control tumors.

The third poster, titled, "Novel combination therapies against AML with 3q26 lesions and EVI1 overexpression," will be presented virtually by Christine Birdwell, Research Scientist, MD Anderson Cancer Center on Tuesday April 12, 2022, at 9:00 a.m., CDT. The poster describes a study examining the potential for tegavivint as a therapy against AML models harboring 3q26 lesions and EVI1 overexpression. EVI1 overexpression is known to confer poor response to therapy and, subsequently, inferior relapse-free and overall survival in AML. As reported in the poster, in vitro treatment with tegavivint dose-dependently induced apoptosis in AML cell lines and patient-derived AML cells with 3q26.2 lesions with and without monosomy. Furthermore, in vivo studies demonstrated that tegavivint combined with BCL2 inhibitor, venetoclax, significantly reduced AML burden and improved overall survival in mouse models, without toxicity, compared to treatment with each drug alone.

On April 8, 2022 Second Genome, a biotechnology company that leverages its proprietary platform to discover and develop precision therapies and biomarkers, reported data demonstrating the Company’s CXCR3 chemokine receptor modulator, SG-3-06686 (referred to as SG-3-00802DC in the AACR (Free AACR Whitepaper) presentation), enhances effector T cell migration to improve the immune system’s activity against tumors, and showed anti-tumor activity in preclinical models as a monotherapy and in combination with anti-Programmed Death Protein-1 (PD-1) treatment (Press release, Second Genome, APR 8, 2022, View Source [SID1234611794]). The data is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held April 8–13 virtually and in New Orleans, Louisiana.

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"We are excited about our pre-clinical data that show the ability of this potential mechanism to go beyond checkpoint blockade as an emerging new immunologic strategy for treating cancers. Checkpoint inhibitor therapy has been transformative for the clinical outcome of cancer patients and additional new checkpoint targets, such as TIGIT/LAG3, continue to be added to this important treatment approach. However, if the proper immune cells are underrepresented or lacking in the tumor microenvironment, these interventions tend to be less effective, and a significant portion of patients have limited or transient benefit. To augment and improve anti-tumor efficacy, we need to develop new therapeutics to better facilitate the ability of effector cells to access the tumor microenvironment. CXCR3 pathway modulation is a well validated and exciting approach to potentially enhance effector cell recruitment and improve existing immunotherapy interventions," said Joe Dal Porto, Ph.D., Chief Scientific Officer of Second Genome. "We look forward to submitting an investigational new drug (IND) application for SG-3-06686, a potential first in class CXCR3 immune modulator, in early 2023."

This data presentation can be accessed during the online-only poster session at the AACR (Free AACR Whitepaper). The information is provided below:

Session Category: Clinical Research Excluding Trials
Session Title: Immuno-oncology
Abstract Number: 6349
Title: Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the
immune system to enhance anti-tumor immunity

SG-3-06686 is a potent CXCR3 chemokine receptor engager that acts as a positive allosteric modulator to increase receptor activity to the three known ligands (CXCL9/10/11). It has demonstrated to increase the activity of CXCL11 on CXCR3 activation by greater than 10-fold from a nM to a pM range with similar effects on CXCL9 and CXCL10. This activity in turn drives strong antitumor activity in several preclinical cancer models.

The poster (#6349) entitled, "Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the immune system to enhance anti-tumor immunity," will be available for on-demand viewing on the AACR (Free AACR Whitepaper) website and will also be made available on the Company’s website at View Source