aTyr Pharma Presents Preclinical Research Demonstrating Treatment with ATYR2810 Inhibits Tumor Growth and Therapy Resistance in Highly Aggressive Cancers at the 2023 AACR Annual Meeting

On April 17, 2023 aTyr Pharma, Inc. (Nasdaq: LIFE), a biotherapeutics company engaged in the discovery and development of first-in-class medicines from its proprietary tRNA synthetase platform, reported a poster presentation at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held April 14 – 19, 2023, in Orlando, FL (Press release, aTyr Pharma, APR 17, 2023, View Source [SID1234630185]). The abstract is available on the AACR (Free AACR Whitepaper) website. The poster will be available on the aTyr website once presented.

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!

The poster presents preclinical findings characterizing the inhibition of tumor growth and therapy resistance in aggressive cancers overexpressing VEGF-C treated with ATYR2810, a fully humanized monoclonal antibody that selectively and functionally blocks neuropilin-2 (NRP2) and VEGF-C signaling by directly binding at the site of the VEGF binding pocket. Treatment with ATYR2810 monotherapy and in combination with chemotherapy in a model of non-small cell lung cancer demonstrated increased tumor growth inhibition and sensitivity to chemotherapy. In a model of clear cell renal cell carcinoma, ATYR2810 in combination with the VEGFR-targeted therapy sunitinib inhibited tumor growth and led to tumor regression in some cases. These data demonstrate the potential therapeutic effects of blocking the NRP2/VEGF-C signaling axis with ATYR2810 on enhanced tumor growth inhibition and sensitivity to chemotherapy and targeted therapy.

"High levels of VEGF-C are known to be associated with key features of aggressive cancers, including therapy resistance, whether this resistance is intrinsic or acquired throughout the treatment paradigm," said Leslie A. Nangle, Ph.D., Vice President, Research, at aTyr. "While current targeted agents can block VEGF/VEGFR signaling, they do not act on VEGF/NRP2 signaling that can occur in the absence of VEGFR and is known to be a key driver of aggressive cancer. By directly blocking the interaction between VEGF and NRP2, ATYR2810 may be an effective novel therapeutic that combats resistance and reduces invasion and metastasis and may serve as a differentiated approach to targeting aggressive cancers."

Details of the poster and corresponding abstract are as follows:

Title: Resistance to cancer therapy via upregulation of the NRP2/VEGF-C axis can be neutralized by ATYR2810
Authors: Alison Barber, Zhiwen Xu, Lisa Eide, Clara Polizzi, Max Pastenes, Lauren Guy, Jasmine Stamps, Kristina Hamel, Zachary Fogassy, Sofia Klopp-Savino, Esther Chong, Yang Qing, Lara Glendening, Christoph Burkart, Leslie Nangle. aTyr Pharma.
Abstract Presentation Number: 1758
Session Title: Reversal of Drug Resistance
Session Date and Time: Monday, April 17, 2023 from 9:00AM – 12:30PM ET
Location: Orange County Convention Center, W Halls B – E1, Poster Section 21
Poster Board Number: 23

About ATYR2810

ATYR2810 is a fully humanized monoclonal antibody that is designed to specifically and functionally block the interaction between neuropilin-2 (NRP2) and one of its primary ligands, VEGF. NRP2 is a cell surface receptor that is highly expressed in certain tumors, in the lymphatic system and on key immune cells implicated in cancer progression. Increased NRP2 expression is associated with worse outcomes in many cancers. VEGF is a validated mediator of tumor survival and growth and correlates with tumor invasiveness and metastasis. Current therapies that directly target classic VEGF/VEGFR signaling do not block NRP2/VEGFR signaling. ATYR2810 is in preclinical development for the treatment of aggressive cancers where NRP2 is implicated.

Precigen Presents Preclinical Data for the Next Generation Mesothelin UltraCAR-T® with Intrinsic PD-1 Blockade at the AACR Annual Meeting 2023

On April 17, 2023 Precigen, Inc. (Nasdaq: PGEN), a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported preclinical data for the next generation UltraCAR-T platform utilizing MSLN CAR from Precigen’s library of non-viral plasmids at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Precigen, APR 17, 2023, View Source [SID1234630184]). The abstract titled, "Next Generation UltraCAR-T Cells with Intrinsic Checkpoint Inhibition and Overnight Manufacturing Overcome Suppressive Tumor Microenvironment Leading to Sustained Antitumor Activity" will be presented as a poster presentation on Monday, April 17, 2023 from 9:00 AM to 12:30 PM ET (Abstract #1791).

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!

Next Generation MSLN UltraCAR-T

UltraCAR-T cells are engineered to co-express a CAR, membrane bound IL-15 (mbIL15), and kill switch genes using non-viral gene transfer via the high-throughput UltraPorator system. UltraCAR-T cells offer the potential for enhanced potency, safety and scalability. Next generation MSLN UltraCAR-T cells also incorporate a novel mechanism for blockade of PD-1, to potentially supersede the need for combination therapy with checkpoint inhibitors and mitigating classic T cell exhaustion that occurs from chronic stimulation, thereby expanding the therapeutic window for efficacy. MSLN has limited expression in normal healthy tissue but is commonly overexpressed on multiple solid tumors such as mesothelioma, ovarian cancer and pancreatic cancer and is associated with poor prognosis making it an attractive anti-tumor target.

Preclinical Summary Results

Next generation MSLN UltraCAR-T cells were successfully engineered using a single multicistronic non-viral transposon and overnight manufacturing process to simultaneously express a CAR, mbIL15, a kill switch, and a novel mechanism for intrinsic PD-1 blockade. Next generation MSLN UltraCAR-T cells showed specific and significant downregulation of PD-1 leading to significant increase in cytotoxicity of MSLN+ PD-L1+ tumor cells in vitro at low effector to target cell ratios compared to control MSLN CAR-T cells lacking PD-1 blockade. Next generation MSLN UltraCAR-T cells exhibited markedly enhanced polyfunctionality as well as enhanced inflammatory cytokine production in the presence of MSLN+ PD-L1+ tumor cells.

In two different in vivo xenograft models, MSLN+ PD-L1+ ovarian cancer and MSLN+ PD-L1+ mesothelioma, a single administration of next generation MSLN UltraCAR-T cells to tumor bearing mice resulted in robust UltraCAR-T cell expansion and durable persistence leading to significant antitumor efficacy. Moreover, rechallenging the previously treated mice who became tumor-free for a second time with mesothelioma tumors to simulate tumor relapse led to the significant reduction in tumor burden without additional MSLN UltraCAR-T treatment demonstrating the durable persistence and functionality of UltraCAR-T cells in vivo.

In mice, the next generation MSLN UltraCAR-T cells demonstrated significant downregulation of PD-1 and preferred CAR-T phenotype that was most similar to T central memory (TCM) and stem cell memory (TSCM). These data demonstrate the potential of UltraCAR-T cells to persist long-term in vivo, prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability for continued response upon tumor rechallenge.

"Precigen has built one of the most comprehensive clinical and preclinical CAR-T portfolios with antigen-specific targets spanning both hematological and solid tumors, including CD33, MUC16, ROR1, CD19, BCMA and MSLN," said Helen Sabzevari, PhD, President and CEO of Precigen. "MSLN is the second target for the next generation UltraCAR-T incorporating intrinsic checkpoint inhibition, following our recently initiated Phase 1/1b study for PRGN-3007. With every milestone, we move closer to our ultimate vision to transform the personalized cell therapy landscape using Precigen’s library approach to target tumor-associated antigens to address unmet medical needs for cancer patients."

Merus’ Petosemtamab Interim Data Demonstrates Clinically Meaningful Activity in Previously Treated Head and Neck Squamous Cell Carcinoma (HNSCC)

On April 17, 2023 Merus N.V. (Nasdaq: MRUS) ("Merus", "the Company", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported interim clinical data as of a February 1, 2023 data cutoff, from the ongoing phase 1/2 trial of the bispecific antibody petosemtamab in previously treated head and neck squamous cell carcinoma (HNSCC) (Press release, Merus, APR 17, 2023, View Source [SID1234630183]). The Plenary Session presentation by Dr. Ezra EW Cohen, Moores Cancer Center, UC San Diego Health, will occur today at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place in Orlando, Florida.

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!

Petosemtamab, or MCLA-158, is a human IgG1 Biclonics designed to bind to cancer cells expressing epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5).

"I am excited by this interim dataset that demonstrates the consistent and clinically meaningful activity of petosemtamab in patients with previously treated head and neck squamous cell carcinoma," said Dr. Andrew Joe, Chief Medical Officer at Merus. "This is clinical validation of a first of its kind EGFR and LGR5 targeting agent."

"There is significant unmet medical need in head and neck squamous cell carcinoma," added Dr. Cohen. "Petosemtamab has the potential to be a meaningful medicine and new standard of care for patients with head and neck cancer."

Updated information and observations from plenary presentation of the ongoing phase 1/2 trial include:

As of the February 1, 2023 data cutoff date, 49 previously treated HNSCC patients (pts) were treated with petosemtamab at the recommended phase 2 dose of 1500 mg intravenous every two weeks
Patient population:
Median age was 63 (range of 31-77); 78% were male
Median prior lines of systemic therapy was 2 (range 1-4); including PD-(L)1 inhibitor in 96% of pts, chemotherapy in 94% and platinum-based chemotherapy in 92% of pts; 2 pts received prior cetuximab
Most frequent primary tumor locations were oropharynx (35%), oral cavity (31%), and larynx (16%)
43 pts were evaluable for efficacy, receiving ≥2 treatment cycles (≥8 weeks) with ≥1 post-baseline tumor assessment or experiencing early progressive disease:
Antitumor activity among 43 pts:
Overall responses rate (ORR) was 37.2% (16/43; 95% CI 23%-53.3%) by RECIST 1.1. per investigator assessment, including 15 confirmed partial responses (PR) and 1 confirmed complete response (CR) (ongoing after 20 months)
Disease control rate (CR + PR + stable disease) was 72.1% (31/43; 95% CI 56.3%-84.7%)
Median time to response was 1.8 months (range 0.8-3.5)
Median duration of response was 6.0 months (95% CI 3.7-NC), with 10 of 16 (62.5%) responders ongoing, and 12 of 43 (27.9%) patients overall ongoing at the time of the data cutoff
Median progression free survival was 5.3 months (95% CI 3.7-6.8); with 29 of 43 pts progressing and 14 of 43 pts censored
Median overall survival was 11.5 months (95% CI 7.2-20.6); with 29 of 49 pts still alive at the data cutoff date
Petosemtamab continued to demonstrate a manageable safety profile:
80 pts were treated with 1500 mg petosemtamab every two weeks across dose escalation and expansion cohorts of the study
Gastrointestinal and skin toxicities were mostly mild to moderate
No treatment-related Grade 5 AEs:
Most frequent related AEs were signs and symptoms of infusion-related reactions (IRRs)
74% Grade 1-4, 21% Grade 3-4 (as grouped term)
Mainly occurred during first infusion
6 of 80 pts discontinued on Day 1 due to a Grade 3-4 IRR
For all patients rechallenged after an IRR, rechallenge was successful
IRRs were manageable with prophylaxis/ prolonged infusion (necessary on Day 1 only)
The presentation is now available on the Merus website.

Company Conference Call and Webcast Information
Merus will hold a conference call and webcast for investors on April 17, 2023 at 6:30 p.m. ET. A replay will be available after the completion of the call in the Investors and Media section of our website for a limited time.

Date & Time: April 17, 2023 at 6:30 p.m. ET
Webcast link: Available on our website
Dial-in: Toll Free: 1 (800) 715-9871 / International: 1 (646) 307-19631
Conference ID: 4032258

About Petosemtamab
Petosemtamab, or MCLA-158, is a bispecific Biclonics low-fucose human full-length IgG1 antibody targeting the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab is designed to exhibit three independent mechanisms of action including inhibition of EGFR-dependent signaling, LGR5 binding leading to EGFR internalization and degradation in cancer cells, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity.

Zentalis announces preclinical data supporting Cyclin E1 as a predictive marker for azenosertib treatment at AACR Annual Meeting 2023

On April 17, 2023 ZentalisTM Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, reported preclinical data that supports CCNE1 amplification and / or Cyclin E1 expression as a potential marker for the enrichment of patient populations for treatment with azenosertib, the Company’s potentially first-in-class Wee1 inhibitor product candidate (Press release, Zentalis Pharmaceuticals, APR 17, 2023, View Source [SID1234630182]). These new preclinical data demonstrate that azenosertib drives cancer cell death in Cyclin E1-high tumor cells in vitro and substantially inhibits the growth of Cyclin E1-high, patient-derived, in vivo tumor models.

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!

The findings are being presented today at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, in a poster entitled "Cyclin E1 protein overexpression sensitizes ovarian cancer cells to azenosertib (ZN-c3), a novel, selective and orally bioavailable inhibitor of Wee1." The poster can be found on the Company’s website at this link. The poster presentation details are below.

Session Category: Clinical Research Excluding Trials
Session Title: Biomarkers of Therapeutic Benefit 2
Session Date and Time: Monday, April 17, 2023, 9:00 AM ET – 12:30 PM ET
Location: Section 39
Poster Board Number: 27
Abstract Presentation Number: 2153

"We are excited to present new preclinical data demonstrating the utility of Cyclin E1 as a predictive marker to identify patients likely to respond to azenosertib," said Mark Lackner, Ph.D., Chief Translational Officer of Zentalis. "Our findings suggest that Cyclin E1 expression via gene amplification or independent mechanisms sensitizes ovarian cancer cells to azenosertib alone or in combination with chemotherapy. These data confirm and build upon our prior preclinical work, and the published research of others, and provide additional evidence that supports our ongoing clinical trial studying azenosertib as a monotherapy in patients with Cyclin E1-driven ovarian cancer. These data also support the potential development of companion diagnostics for azenosertib."
The study analyzed data from a panel of patient-derived ovarian cancer cell lines in vitro and in vivo models of ovarian cancer. The results show that high Cyclin E1 protein expression is significantly associated with sensitivity to azenosertib, and that artificial overexpression of Cyclin E1 in cell lines with low endogenous Cyclin E1 expression sensitizes those cells to azenosertib. In addition, the study provides foundational details on the mechanistic basis of Cyclin E1 sensitization to Wee1 inhibition, including that Cyclin E1 overexpression results in accumulation of replication stress biomarkers and that azenosertib sensitivity is mediated by CDK2 activity.

The study also provides supportive data for several relevant standard of care chemotherapy combinations based on in vitro synergy assays and suggests that Cyclin E1 expression is a relevant clinical predictive marker. The Company is conducting an analysis of CCNE1 copy number and Cyclin E1 protein expression in its Phase 1b study of azenosertib in combination with chemotherapy in patients with platinum-resistant ovarian cancer. The Company now anticipates sharing these clinical data in the first half of 2023, in advance of original guidance.

"These encouraging translational results support the use of CCNE1 copy number and / or Cyclin E1 protein expression as predictive markers that have the potential to significantly improve patient outcomes by enabling us to select the right patients for treatment with azenosertib," said Gordon Mills, M.D., Ph.D., Professor of Cell, Developmental and Cancer Biology, Oregon Health and Science University School of Medicine. The Company is collaborating with Dr. Mills on preclinical and clinical studies related to the effects of Wee1 inhibition on replicative stress, cell cycle modulation and DNA repair.
Another poster being presented at AACR (Free AACR Whitepaper) by the Ivy Brain Tumor Center at Barrow Neurological Institute entitled "Tumor Pharmacokinetics, Pharmacodynamics and Efficacy Analysis of Wee1 inhibitor, Azenosertib in Patient-Derived Xenograft Models of Glioblastoma," demonstrates that azenosertib can achieve pharmacologically-relevant intracerebral free-drug concentrations, and that pharmacodynamic activity is observed in a preclinical glioblastoma model. This research underscores the potential of azenosertib as a therapy for a more extensive range of tumor types than those presently under clinical investigation. Once presented, the poster can be found on the Company’s website using this link. The poster presentation details are below.
Session Category: Experimental and Molecular Therapeutics, Chemistry
Session Title: Pharmacokinetics, Pharmacodynamics, and Molecular Pharmacology
Session Date and Time: Monday, April 17, 2023, 1:30 PM ET – 5:00 PM ET
Location: Section 18
Poster Board Number: 19
Abstract Presentation Number: 2796

About Azenosertib

Zentalis’ azenosertib (ZN-c3) has been designed to be a highly potent and selective Wee1 inhibitor.
Azenosertib is currently being evaluated in the clinic for advanced solid tumors and hematological malignancies in the following three therapeutic settings of high unmet medical need: (1) as a monotherapy, (2) in combination with traditional chemotherapy and DNA damaging agents, and (3) in combination with molecularly targeted agents. As a monotherapy, azenosertib is currently being evaluated in a Phase 2 clinical trial in adult women with uterine serous carcinoma (USC), an aggressive form of endometrial cancer that accounts for approximately 10-15% of all endometrial cancers. We are also evaluating azenosertib as a monotherapy in a Phase 2 clinical trial in patients with Cyclin E1 driven high-grade serous ovarian cancer (HGSOC). The Company is evaluating azenosertib as a monotherapy in a Phase 1 dose optimization clinical trial in patients with advanced solid tumors, and plans to declare the recommended Phase 2 monotherapy dose and provide an update on dose optimization activities in the first half of 2023. In chemotherapy combinations, azenosertib is currently being evaluated in combination with each of paclitaxel, carboplatin, pegylated liposomal doxorubicin (PLD) and gemcitabine in four cohorts in a Phase 1b clinical trial in patients with advanced platinum-resistant ovarian, peritoneal or fallopian tube cancer. The Company plans to disclose results from this study in the first half of 2023, in advance of original guidance. Azenosertib is also currently being evaluated in combination with gemcitabine in a Phase 1/2 clinical trial in adult and pediatric patients with relapsed or refractory osteosarcoma. In combination with molecularly targeted agents, the Company is studying azenosertib in combination with GlaxoSmithKline plc’s (GSK’s) PARP inhibitor, niraparib (ZEJULA), in a Phase 1/2 clinical trial in platinum-resistant ovarian cancer patients who have failed PARP inhibitor maintenance treatment as part of a clinical collaboration with GSK. The Company is also collaborating with Pfizer Inc. to evaluate azenosertib in combination with encorafenib and cetuximab, an FDA-approved standard of care known as the BEACON regimen, in patients with BRAF V600E mutant metastatic colorectal cancer in a Phase 1/2 clinical trial.

Xencor Highlights CD28 Bispecific Antibody Platform at AACR Annual Meeting 2023

On April 17, 2023 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported new preclinical data generated from engineered CD28 bispecific antibodies targeting the solid tumor antigens CEACAM5, ENPP3, mesothelin, STEAP1 and Trop-2 (Press release, Xencor, APR 17, 2023, View Source [SID1234630181]). For each molecule, in vitro T cell activation was enhanced in combination with a CD3 T cell engager. The data were presented in a poster titled "Tumor-specific CD28 costimulatory bispecific antibodies enhance T cell activation in multiple solid tumors" (Abstract 2983) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Orlando, Florida.

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!

T cells in the tumor microenvironment require engagement of both their T cell receptor (TCR) and their co-stimulatory receptors, like CD28, to achieve full activation. The CD28 signal is diminished in cancer because tumor cells do not typically express CD28 ligands (i.e., CD80 and CD86), which leads to potentially compromised activity of CD3 T cell engagers or anti-PD1 checkpoint inhibitors.

Xencor has developed a modular XmAb bispecific antibody platform that allows for the rapid generation of drug candidates that co-stimulate CD28 only in the presence of tumor cells and TCR engagement. Xencor’s XmAb bispecific Fc domain serves as a scaffold for a non-superagonist anti-CD28 binding domain and any tumor-associated antigen of interest. Xencor’s Xtend Fc technology further enhances circulating half-life of the antibody.

"Xencor has rapidly generated multiple CD28 co-stimulatory bispecific antibodies with potential broad applicability across a range of solid tumors, and each of these programs has demonstrated compelling activity," said John Desjarlais, Ph.D., executive vice president and chief scientific officer at Xencor. "We are leveraging the plug-and-play nature of our XmAb bispecific antibody platforms to generate and explore additional CD28 drug candidates against a broader universe of solid tumor targets."

The poster will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

About XmAb808 (B7-H3 x CD28)

Xencor is conducting a Phase 1 study of XmAb808 in patients with advanced solid tumors. XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3 and selectively to the CD28 T-cell co-receptor only when bound to tumor cells, which was demonstrated in in vitro studies. Strong potentiation of checkpoint and CD3 cytotoxic activity was also observed in vivo. XmAb808 is a wholly owned Xencor program.