On November 3, 2023 Synthekine Inc., an engineered cytokine therapeutics company, reported new data from preclinical studies of STK-026, its biased IL-12 partial agonist program, during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting in San Diego (Press release, Synthekine, NOV 3, 2023, View Source [SID1234636936]). STK-026 is designed to retain the potent antitumor activity of IL-12 while avoiding its systemic toxicities and is currently in IND-enabling studies.

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"In the quest for developing new and effective cancer treatments, the pro-inflammatory cytokine IL-12 has shown tremendous potential but clinical use of IL-12 is limited by systemic toxicities and a very narrow therapeutic window," said Martin Oft, M.D., chief scientific officer of Synthekine. "Through our deep insights into the biology of IL-12 and our industry-leading cytokine engineering capabilities, we designed STK-026 to uncouple efficacy from the toxicities that are typically seen with wild-type IL-12. The data presented today adds to the growing body of evidence that STK-026’s novel approach, biasing IL-12’s activity toward activated T cells and avoiding hyperactivation of NK cells, has potential to harness anti-tumor efficacy without dose-limiting toxicity."

Title: Preclinical Pharmacodynamic Characterization of STK-026: A Novel IL-12 Partial Agonist for Cancer with Maintained CD8 T cell activity, Reduced NK-mediated Toxicity and an Improved Therapeutic Window
Session Title: Immune-Stimulants and Immune Modulators
Session Date & Time: Friday, Nov. 3, 2023, 9 am – 7 pm PT
Poster Board Number: 1053
Summary & Key Findings:

STK-026 is a biased IL-12 agonist engineered to exhibit preferential activity on antigen-activated T cells, which drive the efficacy of IL-12, while avoiding broad systemic activation of resting T cells and NK cells, which are linked to the toxicity of IL-12.
In tumor bearing mouse models, a mouse surrogate of STK-026 was well-tolerated and showed meaningful anti-tumor efficacy as both a single agent and in combinations. Notably, compared to wild-type IL-12 treatment, STK-026 monotherapy demonstrated a substantial improvement in therapeutic window which was associated with reduced NK activation and systemic cytokine induction.
In cynomolgus macaques, STK-026 was well-tolerated at very high doses (up to 5mg/kg) without signs of CRS. Further, compared to wild-type IL-12, STK-026 treatment resulted in reduced induction of liver enzymes, organ weight gains and lymphocyte activation in peripheral tissues, thus avoiding the detrimental toxicity associated with IL-12 therapy.
Overall, assessments of STK-026 in mouse and cyno show that its properties successfully avoid spikes of early NK activation but still effectively activate T cells. Preclinical studies and pharmacology support the idea that this rebalancing of IL-12 driven innate and adaptive immune responses can achieve efficacy without dose-limiting toxicity.
The poster will be available on Synthekine’s website following presentation at the meeting.

On November 3, 2023 ProfoundBio, a clinical-stage biotechnology company developing novel antibody-drug conjugate (ADC) therapeutics for cancer, reported multiple data presentations at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 38th Annual Meeting (SITC 2023) (Press release, ProfoundBio, NOV 3, 2023, View Source [SID1234636935]). The company shared initial results from the dose escalation portion of an ongoing Phase 1/2 trial of its lead ADC candidate, rinatabart sesutecan (Rina-S; PRO1184), as well as preclinical data on its Protein Tyrosine Kinase 7 (PTK7)-directed ADC PRO1107 and its continued ADC platform innovations.

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"We are thrilled to present proof-of-concept data from our novel sesutecan ADC platform with the initial clinical results for Rina-S," said ProfoundBio Chief Medical Officer Naomi Hunder, M.D. "We believe Rina-S’s encouraging Phase 1 activity and safety data are differentiated within the landscape of emerging targeted therapies for ovarian and endometrial cancers, as Rina-S elicited robust responses at well-tolerated doses in heavily pretreated patients, including in tumors expressing low levels of FRα. These data validate our platform and approach to developing ADCs with the potential for meaningfully improved outcomes for patients."

Abstract #708: A Phase 1/2 Study of Rinatabart Sesutecan (PRO1184), a Novel Folate Receptor Alpha-Directed Antibody-Drug Conjugate, in Patients with Locally Advanced and/or Metastatic Solid Tumors

Presented by Justin A. Call, M.D., of START Mountain Region, West Valley City, UT, on Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m. to 8:30 p.m. PDT

Rina-S is an investigational folate receptor-alpha-(FRα)-directed ADC based on a novel topoisomerase-1 linker-drug currently in Phase 1/2 development for a number of solid tumors. Key findings from initial Phase 1 clinical results of the Rina-S trial include data from 36 patients treated at dose levels from 60 mg/m2 to 180 mg/m2 administered every 21 days.

Enrolled patients had the following tumor types: ovarian cancer (n=17), endometrial cancer (n=9), breast cancer (n=3), non-small cell lung cancer (n=5), and mesothelioma (n=2).
Patients in the study were heavily pretreated with a median of 4.5 prior therapies; patients with ovarian cancer had a median of 6 prior therapies and patients with endometrial cancer had a median of 4 prior therapies.
Safety and activity highlights include:

Rina-S was well tolerated at doses from 60 mg/m2 to 120 mg/m2, with 140 mg/m2 still under evaluation as a potential maximum tolerated dose; the most common treatment-related adverse events (TRAEs) included cytopenias, gastrointestinal adverse events, and fatigue and were both reversible and manageable. Most TRAEs were Grade 1 or 2.
No interstitial lung disease, pneumonitis, infusion-related reactions, or corneal toxicity were observed.
Among 21 response-evaluable patients with ovarian and endometrial cancer, unselected for FRα expression, an initial objective response rate of 38% was observed (1 complete response (CR), 7 partial responses (PR)); an additional 9 patients had stable disease (SD), including 7 with decreasing tumor measurements, for a disease control rate (CR+PR+SD) of 81%.
Antitumor activity was seen across the full spectrum of FRα expression, with objective responses observed in 8 out of 12 (67%) response-evaluable patients with ovarian and endometrial cancer having >1% FRα expression in their tumors, including 3 PRs in 3 patients with FRα expression below 25% 1+ IHC staining intensity.
Responses were observed across a wide dose range from 60 to 140 mg/m2, with responses deepening over time for most patients.
One patient with ovarian cancer had prior treatment with mirvetuximab soravtansine (Elahere) and had a CR after receiving two doses of Rina-S.
Additional patients are being evaluated in Part A and Part B at multiple dose levels to further optimize the dose.

LD343 Platform and PRO1107 Preclinical Data Presentations, and PRO1160 Trial-In-Progress Presentation:

Abstract #1407: Expanding the Therapeutic Index of MMAE-Based Antibody-Drug Conjugates (ADCs) with a Novel Linker System (LD343)

Presented by Zhu Chen, Ph.D., ProfoundBio Chief Scientific Officer, on Friday, November 3, 2023, Exhibit Halls A and B1, 9 a.m. to 7:00 p.m. PDT

Data from ADCs incorporating ProfoundBio’s novel LD343 platform (a next-generation hydrophilic MMAE-based linker-drug) at a homogeneous drug-to-antibody ratio of 8 (DAR8) compared head-to-head with DAR4 vedotin ADCs highlights the potential to widen the therapeutic index of the clinically validated payload, MMAE.

Data highlights include:

ADCs incorporating the highly hydrophilic LD343 at DAR8 conferred improved physicochemical properties and PK/PD characteristics relative to vedotin.
LD343 ADCs demonstrated antitumor activity in multiple tumor types, with higher in vivo potency than vedotin even at double the amount of dosed payload.
LD343 enabled enhanced delivery of payload to tumor tissue and reduced exposure of payload in circulation.
LD343 enabled an approximately 4-fold increase in the tolerated drug load compared to vedotin ADCs in rats.
Abstract #1406: A Novel PTK7-Directed Antibody-Drug Conjugate (ADC) PRO1107 Demonstrated Broad Antitumor Activity with a Promising Safety Profile in Preclinical Models

Presented by Zhu Chen, Ph.D., ProfoundBio Chief Scientific Officer, on Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m. to 8:30 p.m. PDT

The poster presentation for the anti-PTK7 ADC, PRO1107, highlights preclinical data for this ADC which incorporates LD343 at DAR8.

Data highlights include:

Superior tumor growth inhibition and tolerability relative to the precedent PTK7-directed ADC cofetuzumab pelidotin were observed in head-to-head preclinical studies.
Enhanced preclinical antitumor activity and tolerability are believed to be attributed to PRO1107’s increased hydrophilicity and improved physicochemical properties, augmented delivery of payload to the tumor, less systemic exposure of free payload, and a robust bystander antitumor effect.
Pharmacokinetics demonstrated PRO1107’s stability to be similar to that of the parent antibody.
Abstract #718: Phase 1/2 Study of PRO1160, a CD70-Directed Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors and Hematologic Malignancies

Presented by Sharon Ma, MPH, ProfoundBio Director of Clinical Operations, on Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m. to 8:30 p.m. PDT

The trial-in-progress poster presentation for the anti-CD70 sesutecan ADC, PRO1160, describes the currently recruiting PRO1160-001 Phase 1/2 study (NCT05721222) in patients with solid and liquid tumors.

About Rinatabart Sesutecan (Rina-S, PRO1184)

Rina-S is an ADC comprised of a folate receptor-alpha-directed antibody conjugated to sesutecan, ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, LD038, at a homogeneous drug-to-antibody ratio (DAR) of 8. Exatecan is a highly potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect that has been extensively studied as a small molecule anticancer agent. Sesutecan is a highly hydrophilic stable, cleavable linker designed to mask the hydrophobicity of conjugated exatecan on the ADC, enabling high DAR and efficient delivery of the exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC.

About the PRO1184-001 trial (NCT05579366)

This is a Phase 1/2 study of PRO1184, a folate receptor-alpha-(FRα) targeted antibody-drug conjugate, to evaluate the safety, tolerability, PK, and antitumor activity of PRO1184 in patients with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma. The study consists of two parts, Part A: Dose Escalation and Part B: Dose Expansion.

About PRO1107

PRO1107 is an ADC comprised of a Protein Tyrosine Kinase 7 (PTK7)-targeted antibody conjugated to ProfoundBio’s novel, proprietary hydrophilic MMAE-based linker-drug, LD343, at a homogeneous DAR of 8. MMAE is a potent, membrane permeable microtubule inhibitor that has been clinically validated as an ADC payload by multiple vedotin-based ADCs incorporating MMAE at a DAR of 4. LD343 is a highly hydrophilic stable, cleavable linker designed to mask the hydrophobicity of conjugated MMAE on the ADC, enabling high DAR and efficient delivery of the MMAE payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC. The investigational new drug (IND) application for PRO1107 has been cleared by FDA and its Phase 1/2 clinical trial is expected to begin enrollment in early 2024.

On November 3, 2023 Genialis, the RNA-biomarker company, reported new data detailing how RNA sequencing data can help elucidate tumor biologies that may be amenable to immunotherapies and targeted agents (Press release, Genialis, NOV 3, 2023, View Source [SID1234636934]). The information was presented in two posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting.

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In the first poster with Exact Sciences, Genialis found the Xerna TME Panel, an RNA-based pan-tumor biomarker previously shown to be predictive of responses to multiple immune-targeted cancer therapies, identified 49.4 percent of colorectal cancer patients (N = 336) as having immune biological features that may benefit from immunotherapy. By contrast, only 11 percent and 9 percent were TMB- or MSI-High, respectively. Many of these patients also harbor genetic alterations that have associated targeted therapy options, opening up the opportunity for novel combined therapeutic approaches.

In a second presentation, Genialis introduced its ResponderID MSI program, demonstrating how a machine learning-based classifier of microsatellite instability (MSI) from RNA sequencing data performs comparably to state of the art IHC- and PCR-based MSI detection methods. The Genialis model yielded a mean AUC ROC of 0.96, with all but one validation dataset >0.94. The MSI classifier is tumor-type agnostic, and does not require matched normal samples, as is the case for some PCR-based methods. The Genialis RNA-Seq pipeline solves the need for a fast, accurate, and accessible NGS-based method for MSI detection, aiding in the identification of patients that may benefit from immune checkpoint inhibitor therapy.

"RNA biomarkers provide more comprehensive and dynamic insights into cellular states and regulatory processes compared with DNA or protein biomarkers. And in the case of these two posters, Genialis is showing how using an RNA-based approach helps identify subsets of patients who may benefit from immunotherapy treatment," said Mark Uhlik, Ph.D., VP of Biomarker Discovery. "Genialis has been successful in developing RNA-based biomarkers for myriad cancer types and drug targets, and we are committed to apply our use of cutting-edge technology to aid in the development of potentially life-saving therapies."

Genialis is expert at developing RNA-based patient classifiers, a largely underutilized analyte in clinical diagnostics. Genialis ResponderID draws on multimodal datasets, including RNA-seq data, and employs ML/artificial intelligence (AI) to analyze changes in tens or hundreds of genes relevant to disease pathology. The proprietary algorithms built into ResponderID then identify patterns of RNA transcription that characterize the underlying biology of disease states and the patient’s likely response to therapeutics. By probing the interactions of the underlying disease biologies, ResponderID biomarkers reflect complex disease phenotypes.

Genialis Abstract #219, "Prevalence of genomic alterations in Xerna tumor microenvironment subtypes in colorectal cancer patients," and Abstract #179, "Profiling microsatellite instability using RNA sequencing data" will be on display at the San Diego Convention Center during SITC (Free SITC Whitepaper) 2023. For more information on ResponderID or to make an appointment with Genialis to learn more, please visit www.genialis.com

On November 3, 2023 TriSalus Life Sciences Inc., (Nasdaq: TLSI), an oncology company integrating its novel delivery technology with immunotherapy to transform treatment for patients with liver and pancreatic tumors, reported initial positive safety and feasibility data from a Phase 1 trial at the Society of Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) 2023 Annual Meeting (Press release, TriSalus Life Sciences, NOV 3, 2023, View Source [SID1234636933]).

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TriSalus is studying an investigational class C toll-like receptor-9 (TLR9) agonist, SD-101, delivered intravascularly using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials (periotrial.com). In PERIO-03, SD-101 is delivered via PEDD with the TriSalus Infusion System using a retrograde venous approach, leveraging established interventional radiology access techniques.

The TriSalus Infusion System has an expandable SmartValve and can interface with standard invasive blood pressure transducers for continuous pressure monitoring during infusion of a therapeutic. During infusion, the device blocks retrograde flow and modulates pressure in the vessel, resulting in the perfusion of the venous and capillary network isolated by the device.

Early safety and feasibility data from the PERIO-03 locally advanced pancreatic adenocarcinoma trial revealed that in three patients who received SD-101 via retrograde venous infusion PEDD at the lowest dose level (0.5 mg), there were no serious grade 3/4 adverse events related to treatment. This is a first-in-human experience for use of PEDD and retrograde venous infusion for delivery of an immunologic agent into pancreatic tumors. Immune signals pointed to a decrease in myeloid derived suppressor cells (MDSC) activity in the treated pancreatic tumors, with declines in MDSC associated genes, including arginase-1, nitric oxide synthetase-2, and S100A9 (n=3). Signals associated with T cell activation were also noted in pancreatic tumor biopsy specimens.

"There is a critical need for novel treatments and approaches in locally advanced pancreatic cancer. The PERIO-03 trial is a highly innovative and multidisciplinary approach of delivery of a novel immunotherapy into the pancreas through pancreatic retrograde venous infusion," stated Michael S. Lee, M.D., associate professor of Gastrointestinal (GI) Medical Oncology at The University of Texas MD Anderson Cancer Center. "The treatments have been well tolerated and the translational studies show intriguing changes in immune markers. We are excited to continue enrolling patients in this study."

"These data offer additional validation of our innovative immunotherapy approach for pancreatic tumors. SD-101 was selected based on its mechanism of action, which has the potential to reverse immunosuppression in the pancreas through depletion of MDSC in concert with broad stimulation of immune cells in the tumor microenvironment," said Steven C. Katz, M.D., FACS, Chief Medical Officer at TriSalus. "TriSalus delivery systems, which use the PEDD method, are designed to overcome mechanical barriers to immunotherapy success, which may be underappreciated factors in limiting performance of TLR agonists in liver and pancreas tumors. Pancreatic tumors in particular contain very dense stromal tissue, which may accentuate the mechanical barriers to effective drug delivery in these patients."

Overall, the data emerging from PERIO-03 trials indicate immunologic changes are occurring within the pancreas, with a favorable safety profile. Additionally, pre-clinical data presented by TriSalus at SITC (Free SITC Whitepaper) indicates that SD-101 administered via PEDD can enable both intravenously and subcutaneously administered checkpoint inhibitors.

TriSalus will also present data from its PERIO-01 trial for uveal melanoma liver metastases at a SITC (Free SITC Whitepaper) late breaker session on Saturday, November 4 at 11:25 am PT. All TriSalus presentations from SITC (Free SITC Whitepaper) are available here following their respective sessions.

About Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials

The Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials are studying an investigational class C toll-like receptor-9 agonist, SD-101, delivered intravascularly by TriSalus’ TriNav Infusion System (TriNav) using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials.

The PERIO-01 Phase 1 clinical study for uveal melanoma with liver metastases (UMLM), is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-02 Phase 1b clinical study for hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-03 Phase 1 clinical study for locally advanced pancreatic adenocarcinoma, is studying SD-101 delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

On November 3, 2023 AbCellera (Nasdaq: ABCL) reported new data on its T-cell engager (TCE) programs in two poster presentations at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting (Press release, AbCellera, NOV 3, 2023, View Source [SID1234636932]). The data illustrate how AbCellera is leveraging its TCE platform to discover and develop immuno-oncology therapeutics for multiple tumor targets.

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In its first poster, AbCellera presented data demonstrating that TCE function is determined by multiple factors, including—but not limited to—CD3-binding affinity. Based on these findings, AbCellera developed a high-throughput process that prioritizes TCE function to streamline the selection of diverse CD3-binding antibodies for different tumor targets. AbCellera is currently leveraging its integrated platform to discover and develop TCEs for multiple programs. The poster included data from two of these programs targeting prostate-specific membrane antigen (PSMA) and melanoma-associated antigen 4 (MAGE-A4).

"Altering the affinity of either a small set of CD3-binding antibodies, or an antibody such as SP34-2, is a frequently used strategy to reduce risk of cytokine release syndrome by TCEs. However, we have demonstrated that CD3 affinity alone is not sufficient to optimize TCE function," said Bo Barnhart, Ph.D., VP of Translational Research at AbCellera. "By pairing functionally diverse CD3-binders with a wide range of tumor-binding arms, our TCE platform has identified promising bispecific molecules."

In its second poster, AbCellera presented additional data on its MAGE-A4 x CD3 program, which targets MAGE-A4, a challenging peptide-MHC target. AbCellera used its bispecific platform, OrthoMabTM, to engineer more than 200 bispecific TCEs. Results from high-throughput assessment of these molecules demonstrate that the platform can generate high-quality TCEs for further development.

"Since launching our TCE platform in 2021, we’ve gained a deeper understanding of TCE biology that we believe will enable us to rapidly bring best-in-class molecules to the clinic," said Neil Aubuchon, Chief Commercial Officer at AbCellera. "We look forward to applying these lessons to targets as we work towards bringing better cancer treatments to patients faster."

AbCellera’s poster presentations are available for download here.

About T-Cell Engagers

CD3 T-cell engagers are bispecific antibodies that guide the immune system to find and eliminate cancer cells by binding both cancer-killing T cells and tumor targets at the same time. Developing effective T-cell engagers requires two parental antibodies—a CD3-binding arm that fine-tunes T-cell activation and a tumor-binding arm with high specificity for cancer cells. The small number of available CD3-binding antibodies that can effectively fine-tune T-cell responses has been a barrier to T-cell engager development. To address this barrier, AbCellera developed a complete T-cell engager platform that includes fully human, developable CD3-binding antibodies with unique binding and functional properties. By combining these antibodies with OrthoMabTM, its clinically validated multispecific engineering platform, and its antibody discovery and development engine, AbCellera’s T-cell engager platform is designed to bring new cancer medicines to the clinic faster.