Nimbus Therapeutics Announces Initiation of First-in-Human Clinical Trial with NDI-219216, Novel WRN Inhibitor for MSI-H Tumors

On April 25, 2025 Nimbus Therapeutics, LLC ("Nimbus Therapeutics" or "Nimbus"), a biotechnology company that designs and develops breakthrough medicines through its powerful computational drug discovery engine, reported that its Phase 1/2 clinical trial of NDI-219216, the company’s investigational non-covalent Werner syndrome helicase (WRN) inhibitor, is actively enrolling and dosing patients with advanced solid tumors (Press release, Nimbus Therapeutics, APR 25, 2025, View Source [SID1234652169]).

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"The initiation of this clinical trial marks an important milestone in advancing our novel WRN inhibitor program," said Anita Scheuber, M.D., Ph.D., Senior Vice President, Therapeutic Head, Oncology at Nimbus. "We are excited to be evaluating NDI-219216 in patients with advanced disease, who currently have limited treatment options when they experience disease progression on standard of care therapies. The trial is actively enrolling across multiple clinical sites, and we look forward to generating important additional safety and efficacy data as we advance this promising candidate through clinical development."

The Phase 1/2 clinical trial (NCT06898450) is an open-label, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of NDI-219216 in patients with advanced cancer. The study will be conducted in three parts: Part A (dose escalation), Part B (dose optimization), and Part C (dose expansion).

Nimbus presented promising preclinical data on NDI-219216 (previously NTX-452) at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in October 2024. The data demonstrate that NDI-219216 is a potent and selective WRN inhibitor with significant tumor regression and sustained complete responses observed at low doses in MSI-H tumor models refractory to immunotherapy and chemotherapy.

The company will present new findings comparing covalent versus non-covalent WRN inhibition mechanisms and demonstrating NDI-219216’s superior efficacy across multiple preclinical MSI-H tumor models compared with other clinical-stage WRN inhibitors in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 25-30, 2025 in Chicago. The poster entitled "NDI-219216: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors" highlights key preclinical findings related to NDI-219216, including:

Demonstration of activity against a potential resistance mutation at Cysteine 727 that could significantly reduce the efficacy of covalent WRN inhibitors
Robust tumor regression across multiple MSI-H tumor models, including those that are refractory to existing standard of care agents
Superior efficacy at lower doses and in less responsive MSI-H tumor models compared to other clinical-stage WRN inhibitors
"The data we are presenting at AACR (Free AACR Whitepaper) 2025 highlight several important features of our non-covalent WRN inhibitor," said Peter J. Tummino, Ph.D., President of Research and Development at Nimbus. "NDI-219216 has the potential for more durable target engagement than covalent inhibitors and maintains potency against potential resistance mutations. Its superior efficacy across multiple MSI-H tumor models, including those less sensitive to other WRN inhibitors and those refractory to current therapies, reinforces our belief that NDI-219216 represents a best-in-class opportunity with broad potential across multiple MSI-H tumor types with significant unmet need."

About NDI-219216

NDI-219216 is a highly potent and selective non-covalent investigational inhibitor of Werner syndrome helicase (WRN) activity being developed for the treatment of MSI-H tumors. WRN is a DNA helicase required for DNA replication and DNA repair and is a validated synthetic lethal target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of deficient mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric, and endometrial cancers. In preclinical studies, treatment with NDI-219216 exhibited robust antitumor activity across multiple cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) MSI-H tumor models, including models for colorectal, gastric, and endometrial cancers.

Zai Lab Presents Data Highlighting Potential of Internally Developed, Next-Generation Oncology Therapies at AACR 2025

On April 25, 2025 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported that it will present new data from studies evaluating two of its internally developed, next-generation, investigational oncology therapies that it has global rights to, ZL-6201, a novel leucine-rich repeat-containing protein 15 (LRRC15) antibody-drug conjugate (ADC) targeting multiple solid tumors, and ZL-1222, an innovative anti-PD-1/ interleukin-12 (IL-12) immunocytokine for cancer immunotherapy, during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 in Chicago, Illinois this week (Press release, Zai Laboratory, APR 25, 2025, View Source [SID1234652168]). The data provide strong evidence supporting continued evaluation of both investigational therapies.

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"The latest findings that will be presented at AACR (Free AACR Whitepaper) 2025 demonstrate impressive potential for the continued advancement of these next-generation oncology therapies," said Linda Liu, Ph.D., Senior Vice President, Biologics Discovery, Zai Lab. "We look forward to continuing our evaluation of these therapies that may provide the opportunity to broaden treatment options for patients who have been unresponsive or resistant to current treatments across a broad range of cancer types."

ZL-6201 is a potential first- and best-in-class ADC with high affinity and specificity for LRRC15, an appealing target for cancer therapy due to its overexpression in multiple solid tumor types such as sarcoma, glioblastoma and melanoma. The compound was designed with a novel ADC technology platform called TMALIN, which leverages the tumor microenvironment to overcome challenges associated with first-generation ADC therapies, including off-target payload toxicity.

Findings to be presented at AACR (Free AACR Whitepaper) 2025 on Tuesday, April 29, demonstrate that ZL-6201 efficiently internalizes within and kills tumor cells, while also exhibiting a strong bystander killing effect in the tumor microenvironment where the target is often expressed. In multiple in vitro and in vivo pre-clinical studies, treatment with ZL-6201 effectively suppressed the growth of established tumors. Based on these findings, Zai Lab plans to initiate Investigational New Drug (IND)-enabling studies of ZL-6201 as a potential treatment for patients with sarcoma and other LRRC15-positive solid tumors, such as breast cancer and other malignancies, in 2025.

ZL-1222 is a PD-1 targeted, next-generation IL-12 immunocytokine designed to leverage the anti-tumor potential of IL-12 while lowering the associated systemic toxicity. Previous preclinical studies have demonstrated that IL-12 can have dramatic anti-tumor activity. However, in clinical investigations, systemic administration of IL-12 has been associated with a narrow therapeutic index with severe adverse events.

Findings from preclinical studies to be presented Monday, April 28, at AACR (Free AACR Whitepaper) 2025 suggest that ZL-1222, through precisely tailored IL-12 activity and PD-1 targeting, demonstrate potent anti-tumor activity in both anti-PD-1 sensitive and resistant tumor models, with improved systemic safety. These results indicate its potential to benefit patients who are unresponsive or resistant to the current immuno-oncology therapies.

"At Zai Lab we are building a robust portfolio of potential first- and best-in-class oncology therapies to expand treatment options for patients around the world," said Rafael G. Amado, M.D., President, Head of Global Research and Development, Zai Lab. "Findings from our preclinical studies of ZL-6201 and ZL-1222 demonstrate our commitment to identifying innovative approaches that address limitations associated with first-generation therapies. These include the ability to deliver higher concentrations of cytotoxic agents and limit off-target toxicity, in order to deliver meaningful treatment options for patients with a range of cancer types."

Details regarding the Zai Lab poster presentations at AACR (Free AACR Whitepaper) 2025 are as follows:

Title: Discovery and characterization of a novel LRRC15-targeting antibody-drug conjugate (ADC) for the treatment of solid tumors
Presenter: Bing Wan, Ph.D., Executive Director, Biology, Zai Lab
Session Title: New and Emerging Cancer Drug Targets
Date/Time: Tuesday, April 29, 2025, from 9:00 a.m. – 12:00 p.m. CT
Location: McCormick Place Convention Center, Poster Section 17
Poster Board Number: 23
Published Abstract Number: 4266

Title: Cis-delivery of a potency-reduced IL-12 via an anti-PD-1 single-chain antibody exhibits potent anti-tumor activity
Presenter: Linda Liu, Ph.D., Senior Vice President, Biologics Discovery, Zai Lab
Session Title: Late-Breaking Research: Clinical Research 1
Date/Time: Monday, April 28, 2025, from 2:00 p.m. – 5:00 p.m. CT
Location: McCormick Place Convention Center, Poster Section 53
Poster Board Number: 1
Published Abstract Number: LB204

City of Hope Scientists Present Leading-Edge Research at American Association for Cancer Research (AACR) Annual Meeting

On April 25, 2025 Researchers with City of Hope, one of the largest and most advanced cancer research and treatment organizations in the U.S. with its National Medical Center named top 5 in the nation for cancer by U.S. News & World Report, reported that it will present more than 74 chaired, plenary, educational, minisymposium, poster and other sessions on innovative clinical trial results, breakthrough diagnostic techniques and advances in treatment options at the AACR (Free AACR Whitepaper) Annual Meeting, which started April 25 and ends April 30 in Chicago (Press release, City of Hope, APR 25, 2025, View Source [SID1234652167]).

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In addition to City of Hope’s innovative research being presented throughout the meeting, David W. Craig, Ph.D., professor and founding chair of the Department of Integrative Translational Sciences within Beckman Research Institute of City of Hope, is chairing the final plenary session of the conference, "Opportunities in Predictive Oncology," on Wednesday from 8 to 10 a.m. CT. He will also present an educational session on using a biological analysis approach called multiomics to investigate the unique genetic makeup of different cell populations in solid tumors on Friday from 4:46 to 5:06 p.m. CT.

On Saturday from 10:00 to 11:30 a.m. CT, Michael A. Caligiuri, M.D., former president of City of Hope National Medical Center and professor in the Department of Hematology & Hematopoietic Cell Transplantation, will chair a session on advances in the application of natural killer (NK) cells and present on "Innate immune lymphocytes, including NK cells." He will also chair "Academic Entrepreneurship: Getting Your Discovery to Patients, Part 1—Liftoff" on Saturday from 8:00 to 9:30 a.m. CT, which will help define the steps required for translating research from the bench to the bedside.

As part of a session on advances in diagnostics and therapeutics, Hope Rugo, M.D., who recently joined City of Hope as director of its Women’s Cancers Program, will talk about new findings in managing toxicities from antibody-drug conjugates on Monday from 1:25 to 1:45 p.m. CT. Dr. Rugo will also serve as a discussant at the Clinical Trials Plenary Session on Biologics and T-cell Engagers on Tuesday from 10:15 a.m. to 12:15 p.m. CT.

Highlights of City of Hope research presented at the AACR (Free AACR Whitepaper) conference include:

Phase 3 clinical trial shows promising results for novel immunotherapy

Cancer of the nasopharynx, or the upper part of the throat that plays a crucial role in breathing and swallowing, is relatively rare. However, in certain regions like China and North Africa, the disease is much more common. To combat recurrent or metastatic nasopharyngeal carcinoma, a new immunotherapy drug has been tested in combination with standard chemotherapy.

Data from a phase 3 clinical trial of the medication called penpulimab resulted in the Food and Drug Administration (FDA) approving its use this past week in combination with cisplatin or carboplatin and gemcitabine for the first-line treatment of adult patients with recurrent or metastatic nasopharyngeal carcinoma. The FDA also approved penpulimab as a single agent for similar patients with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

Medical oncologist Aditya Shreenivas, M.D., M.S. will present the supporting data from "Penpulimab versus placebo in combination with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma: A global, multicenter, randomized, double-blind, phase 3 trial (AK105-304)" during a clinical trials minisymposium session on Sunday from 3:50 to 4:00 p.m. CT.

Penpulimab is an anti-PD-1 inhibitor, a type of treatment that helps the immune system recognize and attack cancer. Building on previous studies that have shown that the combination of PD-1 inhibitors with chemotherapy exhibits promising efficacy as a first-line treatment for Asian patients, phase 3 of the trial included 291 patients from both Asian and non-Asian countries.

Patients received either a combination of penpulimab and standard chemotherapy or a placebo plus chemotherapy. The study’s findings showed that patients who had penpulimab added to their treatment plan had their cancer controlled for 9.63 months on average, compared to just 7.00 months for those who did not. This represents a 55% reduction in the risk of disease progression. The researchers also found that the combination of penpulimab with chemotherapy had a manageable safety profile with tolerable side effects.

"What makes penpulimab unique is that it is an anti-PD-1 antibody with a modified structure designed to potentially improve efficacy while reducing immune-related side effects," said Dr. Shreenivas, who led at the study at City of Hope, one of 46 trial sites worldwide. "This research supports use of penpulimab plus chemotherapy as a new first-line treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma."

He also says that since penpulimab has already been approved in China for some other cancers, like relapsed or refractory classic Hodgkin’s lymphoma and metastatic squamous non-small-cell lung cancer, this study might lead to expanded approvals for penpulimab in additional countries.

According to Dr. Shreenivas, future findings from the clinical trial could include explorations of how to identify which patients benefit most from this treatment, as the researchers analyzed various subgroups including those with liver metastases, different protein expression levels, and different DNA levels of Epstein-Barr virus, which is considered a strong risk factor for nasopharyngeal carcinoma.

The clinical trial was sponsored by Akeso, a Chinese biopharmaceutical company that developed penpulimab.

Researchers use innovative technologies to learn more about treatment responses on ovarian, prostate and breast cancer patients

Ovarian cancer

Not all patients with aggressive, high-grade serous ovarian cancer — the most common type of the disease — respond the same way to immunotherapy. To elucidate differences that might help tailor immunotherapy strategies for individual patients, a group of researchers from City of Hope and USC led by Jing Qian, a doctoral student in the lab of John D. Carpten, Ph.D., City of Hope’s chief scientific officer, Irell & Manella Cancer Center Director’s Distinguished Chair and Morgan & Helen Chu Director’s Chair of the Beckman Research Institute, sought to characterize the cancer and immune cells within the tumor environments of patients with different responses to treatment.

By using spatial transcriptomic technologies to map interactions between cancer and immune cells, the team was able to reveal differing immune cell behavior and composition in tumors with varied responses to immunotherapy. Spatial transcriptomic methods can provide valuable insights into gene expression within tissue and the technology is an area of rapid development in medical research.

"In the future, this approach could help identify patients who are more likely to benefit from immunotherapy and uncover new targets to improve treatment for those who don’t respond," said Qian. "Ultimately, it pushes the field closer to precision immuno-oncology in high-grade serous ovarian cancer."

Next, the team plans to use cell models and additional patient cohorts to explore whether targeting specific immune cell types can improve responses to immunotherapy in ovarian cancer.

Qian will present "Spatial transcriptomics reveals differences in the tumor and immune microenvironment of high-grade serous ovarian cancers with differing responses to immune checkpoint inhibitors" as a late breaking poster session on Sunday from 2:00 to 5:00 p.m. CT.

Prostate cancer

Recent studies suggest that a complex interplay between ethnicity and disease biology could influence how metastatic hormone sensitive prostate cancer (mHSPC) behaves in different patients. To investigate differences in tumor tissue from patients of Hispanic background compared to those not of Hispanic background, a team of City of Hope researchers led by Tanya Barauskas Dorff, M.D., professor in the Department of Medical Oncology & Therapeutics Research, borrowed pre-treatment prostate biopsy specimens from an existing clinical trial.

Using digital spatial profiling, a technology used to study gene and protein expression in tissues, the researchers were able to interrogate the tumor microenvironment from different patients with mHSPC with greater granularity and depth. They found a difference in expression of certain proteins like Foxp3, PARP and STING, all of which are targets of certain cancer medications, between Hispanic and non-Hispanic patients.

"This type of exploration in tissue samples from patients of diverse backgrounds may help uncover factors that could account for differences in treatment response," said Dr. Dorff. "As we complete the testing on additional tissue samples, we hope to compare results against treatment outcomes, to see a clearer signal emerge identifying candidate proteins for future validation."

She said the team hopes to increase the variety of samples being tested and compare their findings to clinical outcomes from the trial, which should become available early 2026.

Peter Zang, M.D., a hematology & oncology fellow and first author on "Digital spatial profiling with GeoMx to identify differential protein expression in Non-Hispanic/Latino and Hispanic/Latino Patients with metastatic hormone sensitive prostate cancer," will present the team’s poster abstract on Tuesday from 2:00 to 5:00 p.m. CT.

Breast cancer

A poster presentation by Sydney Grant, a postdoctoral fellow, and Aritro Nath, Ph.D., assistant professor in the Department of Medical Oncology & Therapeutics Research, on Tuesday from 9:00 a.m. to 12:00 p.m. CT, "Integrating multimodal data with survival-based variational autoencoders to predict recurrence-free survival in breast cancer," will highlight a powerful new AI-based approach the team developed to predict recurrence-free survival in breast cancer patients.

By enhancing existing generative AI models to process a broader range of real-world patient data, which extend far beyond traditional biomarkers currently used in the clinic, Grant and Nath established an approach that enables more accurate and personalized predictions about cancer patient outcomes.

"This work could lead to new clinical tests used at the time of diagnosis to guide treatment decisions and bring us closer to truly personalized care," said Dr. Nath. "For example, these tools would help doctors identify which patients need more aggressive therapy and which patients could avoid overtreatment and unnecessary side effects."

The team is now working to extend their models to predict which types of treatment or drug classes will work best for individual patients, with the goal of guiding therapy selection in the clinic using AI.

New technology identifies unique genetic changes in early-onset colorectal cancer among Hispanic and Latino patients

Colorectal cancer is the second leading cause of cancer-related deaths and cases among younger patients are rising, particularly among Hispanic and Latino populations. A new study from the lab of Enrique Velazquez Villarreal, M.D., Ph.D., M.P.H., M.S., assistant professor in the Department of Integrative Translational Sciences, has found that early-onset colorectal cancer in Hispanic and Latino patients has unique genetic changes that help explain how the cancer grows and spreads.

"This is the first study to look closely at the genetics of colorectal cancer in Hispanic and Latino patients from the Los Angeles area, a group that’s often left out of cancer research," said postdoctoral fellow Francisco (Paco) Carranza, who is first author on the study. "By understanding how colorectal cancer affects different populations, especially those who are often overlooked, we can help create better and more targeted treatments."

To find genetic changes, the research team used DNA and RNA sequencing plus a powerful new technology called 10x Genomics Visium that let them see which genes are turned on or off in specific parts of a tumor. This helped them better understand how cancer cells interact with the immune system and how the disease behaves in this patient population.

"This kind of research brings us closer to making sure all patients—no matter their background—have access to the best possible care and the same chance at successful outcomes," said Dr. Velazquez Villarreal, whose research is focused on addressing colorectal cancer health disparities in Hispanic and Latino communities.

Next, Carranza and his collaborators plan to move this research even closer to patient care by using an advanced version of the 10x Genomics Visium platform that allows researchers to look at tumors one cell at a time to give even more detailed information that could lead to better tailored therapies and help design new clinical trials.

Carranza will discuss the team’s work during a minisymposium session called "Multi-omics analysis of MYC gene and WNT signaling pathway alterations in early-onset colorectal cancer in Hispanic/Latino patients, enhanced with spatial transcriptomics approaches" on Monday from 2:35 to 2:50 p.m. CT.

AI tool developed at City of Hope makes precision medicine more accessible and inclusive

Dr. Velazquez Villarreal will also present a poster on his lab’s development of a new precision medicine AI tool that addresses key challenges in the integration of different data sets to promote better equity in cancer research.

The new tool, called the Precision Medicine Artificial Intelligence Agent (PM-AI), is a conversational AI system that can understand plain-language questions and automatically run complex data analyses. It combines clinical information, genetic data, and social factors like income or access to care to make it easier for scientists to study cancer in a more complete and inclusive way.

"By making it easier to analyze large and complex datasets, PM-AI can help researchers and doctors discover which treatments work best for different groups of people," said Dr. Velazquez Villarreal. This means patients could one day receive more personalized care based on their genetics, health history, and social conditions—leading to better outcomes for everyone, especially underserved communities."

He said the research team plans to keep expanding PM-AI’s capabilities by applying it to more types of cancer and integrating even more kinds of data. The goal is to support clinical decisions, help design new studies and ultimately make precision medicine more accessible for all patients.

The study, "PM-AI agent: A conversational artificial intelligence system for precision medicine and advancing health equity through integrative clinical, genomic and social determinants of health data analysis," is the first accepted by AACR (Free AACR Whitepaper) to use a cutting-edge technology known as an AI-driven conversational agent and will be presented during a poster session on Sunday from 2:00 to 5:00 p.m. CT.

Combination treatment found to overcome therapy resistance in ER+ breast cancer

In patients with estrogen receptor-positive (ER+) breast cancer — the most common type of the disease — 30-50% eventually develop resistance to primary endocrine therapy and progress to advance disease. While cell cycle inhibitor therapies help slow down metastatic ER+ breast cancer, patients often become resistant to these treatments, too.

Now, a new study by City of Hope researchers has revealed that ER+ breast cancers resistant to cell cycle inhibitors undergo dynamical rewiring of both apoptosis (or cell death) pathways and proliferative pathways, which regulate cell division and growth, to survive. To overcome this resistance, the team looked for add-on therapies that target growth factor receptors. Their goal was to find a combination that provides a blockade of proliferative pathways with sustained upregulation of apoptosis pathways to maintain treatment effectiveness.

Using leading-edge integration of short- and long-term biological experimentation cell models with mathematical and computational analysis, they discover a new proposed combination therapy of ribociclib (a cell cycle inhibitor) plus afatinib (a growth factor inhibitor) that can durably control breast cancer cell growth over time.

"Although cell growth-targeted drugs have improved outcomes for hormone-dependent breast cancer patients, resistance remains a major clinical challenge limiting their long-term benefit," said Andrea Bild, Ph.D., professor in the Department of Medical Oncology & Therapeutics Research and senior author of the study. "Our research presents a novel strategy to enhance the durability and effectiveness of current treatments."

Next, the research team aims to translate their findings for patient benefit in the clinic. To do so, Dr. Bild said they will expand their use of temporal computational and mathematical modeling to monitor molecular changes over time and identify dynamic biomarkers that can guide future treatment strategies.

Kimya Karimi, a doctoral student in Dr. Bild’s lab, will present the team’s study "Overcoming intrinsic mechanisms of cell cycle inhibitor resistance in estrogen receptor-positive (ER+) breast cancer" during a minisymposium on Tuesday from 3:05 to 3:20 p.m. CT.

Bexion Pharmaceuticals, Inc. Announces Poster Presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025

On April 25, 2025 Bexion Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company developing a novel class of biologic therapy to treat solid tumor cancers and chemotherapy-induced peripheral neuropathy (CIPN), reported that the Company will participate in the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 taking place April 25-30, 2025, in Chicago, Illinois (Press release, Bexion, APR 25, 2025, View Source [SID1234652166]). Details of the posters are included below.

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First Poster Details:
Abstract Title: Development of an in-house methodology to analyze large clinical cancer biomarkers datasets
Abstract Number: 1105
Poster Board Number: 12
Session Title: Tumor Subtypes and Biomarker Discovery
Session Date: Sunday Apr 27, 2025
Session Time: 2:00 PM – 5:00 PM
Presenter: Dr. Tariq Arshad

Second Poster Details:
Abstract Title: Sphingolipid modulating compounds BXQ-350 and desipramine display synergy in reducing viability across multiple cancer cell types in vitro
Abstract Number: 5439
Poster Board Number: 17
Session Title: Therapeutic Targets and Mitochondrial Function
Session Date: Tuesday Apr 29, 2025
Session Time: 2:00 PM – 5:00 PM
Presenter: Dr. Tariq Arshad

The abstracts are scheduled to be posted to the AACR (Free AACR Whitepaper) Online Program Planner at 4:30 PM ET on Tuesday, March 25.

About AACR (Free AACR Whitepaper)
The American Association for Cancer Research (AACR) (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world.

About BXQ-350
Bexion’s lead drug candidate is BXQ-350, a first-in-class biologic containing the multifunctional sphingolipid activator protein, Saposin C, and a phospholipid. Multiple Phase 1 clinical trials in adult and pediatric patients have demonstrated a robust safety profile for BXQ-350 with evidence of single agent activity across multiple solid tumor types. Additionally, other clinical and non-clinical data suggest BXQ-350 has activity in chemotherapy-induced peripheral neuropathy, an area of high unmet medical need in patients treated with oxaliplatin and other chemotoxic agents.

Precision Biologics to Present Recent Data on a New Antibody-Drug Conjugate (ADC) Utilizing the Monoclonal Antibody (mAb) PB-223, at AACR Annual Meeting 2025

On April 25, 2025 Precision Biologics, Inc. reported preclinical development and characterization of a novel ADC using its anti-core 2 O-glycans anti-human carcinoma mAb PB-223 will be presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, on April 29th, 2025, McCormick Place Convention Center, Chicago, IL, USA (Press release, Precision Biologics, APR 25, 2025, View Source [SID1234652165]).

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Poster title: Development and characterization of an antibody-drug conjugate (ADC) utilizing PB-223, a novel monoclonal antibody (mAb) specifically targeting core 2 O-glycans on human carcinomas

The presentation of the poster will be made in person on the following date and location:

April 29th, 2025, 9am-12pm

McCormick Place Convention Center, Chicago, IL, USA

Session Title: Antibodies and Antibody-Drug Conjugates

Poster Section 36

Abstract Control Number 2878

BACKGROUND:

Antibody-drug conjugates (ADCs) represent a cutting-edge approach in cancer therapy. The three essential components of an ADC include: the mAb, the linker, and the cytotoxic payload. The mAb in current ADCs is usually designated to target specific tumor-associated antigens that are overexpressed on the surface of cancer cells.

Our ADC contains the following components:

The mAb: We used PB-223, an innovative mAb developed through affinity maturation of mAb NEO-102 (Ensituximab), a chimeric human IgG1 mAb that targets truncated core 2 O-glycans, specifically expressed by cancer cells and not by healthy tissues. The binding affinity of PB-223 for its target was improved, compared to NEO-102, by optimizing its VH and VL sequences through Fast Screening for Expression Biophysical Properties and Affinity. PB-223 demonstrated a binding affinity (KD) at least 4-fold lower than NEO-102, indicating stronger tumor binding. An immunohistochemistry analysis also revealed that PB-223 binds to a wider spectrum of tumor tissues compared to NEO-102, including not only colorectal, and pancreatic cancer, but also triple negative breast, prostate, kidney, head and neck, liver, and bladder cancer. Further experiments show PB-223 does not bind to normal tissues and that it can be internalized into human cancer cell lines expressing its target.
The payload: Monomethyl auristatin E (MMAE) was used as payload. MMAE is a potent antimitotic agent that inhibits cell division by blocking the polymerization of tubulin and is the most common ADC payload used to be linked to antibodies in clinical development for oncologic applications.
The linker: mc-vc-PABc was used as linker. PB-223 was conjugated to the linker-payload through a cysteine-based conjugation method.
STUDY PRESENTED AT AACR (Free AACR Whitepaper) 2025:

After development of the ADC we proceeded with its characterization, evaluating the following features:

DAR: The drug-to-antibody ratio (DAR) is crucial to predict the efficacy and safety of ADCs. It is generally believed that a DAR between 2 and 4 is the best choice for ADC drugs. Higher DAR may disrupt the pharmacokinetic properties of ADCs, while lower DAR significantly negatively affects the potency of ADCs. We developed three ADCs: PB-MMAE-2, PB-MMAE-5 and PB-MMAE-6. The DAR for these ADCs was 3.72, 3.92 and 4.15, respectively.
Binding of ADCs to cancer cells expressing core 2 O-glycans: flow cytometry was used for binding assessment of three ADC clones using the human ovarian cancer cell line OV-90 as the target. All three ADCs exhibit similar binding affinity to OV-90 compared to PB-223.
Killing of cancer cells: We evaluated the ability of all three ADC clones to kill OV-90 cells. All three ADCs effectively killed OV-90 cells (80% of cells were dead 5 days after treatment). We then chose one ADC clone, PB-MMAE-5, to test its ability to kill additional human cancer cell lines. Preliminary results show that PB-MMAE-5 can kill human prostate, triple positive and triple negative breast, lung, colon, pancreatic cancer cell lines.
Safety in vivo: We chose the ADC clone PB-MMAE-5 to test its toxicity in rats. The ADC PB-vcMMAE-5 in rats was administered intravenously at a concentration of 2.3 mg/kg as single dose. Animal body weight was measured at different time points until 14 days after ADC administration. The ADC PB-vcMMAE-5 was well tolerated in rats. No sign of distress nor loss of body weight were observed after administration.
Stability in human plasma: Stability of the ADC PB-vcMMAE-5 was evaluated in human plasma. PB-vcMMAE-5 ADC was incubated with male and female human plasma at concentration of 50 µg/mL and 100 µg/mL. Concentration in human plasma was detected by ELISA at 0h, 24h (1 day), 48h (2 days), 96h (4 days), 168h (7 days), 240h (10 days), 336h (14 days). The ADC was stable in human plasma (after 14 days, mean residual rate of PB-vcMMAE-5 ADC in human plasma was 23% for ADC at 100 µg/mL and 22% for ADC at 50 µg/mL).
Efficacy in vivo: The efficacy of the ADC PB-vcMMAE-5 was assessed in OV-90 subcutaneous xenograft model established in NOD-SCID mice. The ADC PB-vcMMAE-5 was administered intravenously at doses 1 mg/kg and 3 mg/kg, once per week for three weeks. Preliminary data suggest that PB-vcMMAE-5 exhibits anti-tumor activity in the NOD-SCID mice tumor model. Two days after the second dose of PB-vcMMAE-5 at 3mg/kg, treated mice showed a significant reduction in tumor volume compared to mice treated with an 1mg/kg dose of PB-vcMMAE-5, PBS or payload alone.
Findings from this study showed that PB-vcMMAE-5 can kill cancer cells expressing PB-223’s target, is not toxic, is effective in vivo, and is stable in human plasma, suggesting that PB-vcMMAE-5 has promising potential as a therapeutic option for a range of human malignancies expressing core 2 O-glycans.