On April 4, 2024 IRBM, a leader in the field of drug discovery, reported that it will be disclosing new data on two of its most promising internal assets at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting occurring in San Diego, April 5-10 (Press release, IRBM, APR 4, 2024, View Source [SID1234641797]). The data will reveal insights into the novel compounds developed to address critical unmet needs in cancer treatment.

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Asset Highlights:

Potential first-in-class Antibody-Drug Conjugate (ADC) targeting CRLF2/TLSPR in "Ph-like" B-ALL (AM E3-SG3249) demonstrated significant preclinical efficacy, representing a pioneering approach to treating hematologic cancer characterized by poor prognosis and high relapse rates, often affecting adolescents.
Potential best-in-class brain permeable SHP2 allosteric inhibitor (I-1000233) exhibited promising results in preclinical studies, offering a new method of treating patients with RAS-driven malignancies, including challenging brain tumors and metastases.
Carlo Toniatti, MD, PhD, Chief Scientific Officer at IRBM, expressed his enthusiasm for the upcoming presentations: "The AACR (Free AACR Whitepaper) meeting presents a unique opportunity for IRBM to share our latest advancements in cancer research with the global scientific community. Our work on the CRLF2/TLSPR targeting ADC and CNS-penetrant SHP2 small molecule inhibitor exemplifies our relentless pursuit of novel therapeutic strategies that can make a significant difference in the lives of patients battling cancer. These developments reflect our deep scientific expertise and innovative spirit, underscoring IRBM’s role as a frontrunner in the integrated drug discovery industry."

The two assets, which have been progressed through the discovery phase within the public-private environment of the National Collection of Chemical Compounds and Screening Center (CNCCS), are a testament to IRBM’s integrated research capabilities, their commitment to advancing science to improve lives, and their pursuit of new and better treatments for cancer.

Details for the poster presentations are listed below.

CNS-penetrant SHP2 inhibitor:
Session Category: Experimental and molecular Therapeutics
Session Title: Kinase and phosphatase Inhibitors 2
Session Date and Time: Monday April 8, 2024, 9:00 AM -12:30 PM
Location: Poster Section 25
Poster Board Number: 24
Published Abstract Number: 1975
Presenter: Francesca Puca, PhD. Principal Research Scientist

CRLF2/TLSPR targeting ADC:
Session Category: Immunology
Session Title: Antibody-Drug Conjugates
Session Date and Time: Monday Apr 8, 2024, 1:30 PM – 5:00 PM
Location: Poster Section 2
Poster Board Number: 13
Published Abstract Number: 2610
Presenter: Claudia Dall’Armi, PhD. Senior Research Investigator

On April 4, 2024 Navrogen, Inc., a biopharmaceutical company specialized in developing therapies for cancer and immune-related disorders, reported that it will be presenting preclinical data on its next-generation anti-CD20 antibody, NAV-006, and ICAM-1 refractory antibody-drug conjugate platform at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference in San Diego, California, on April 8-9 (Press release, Navrogen, APR 4, 2024, View Source [SID1234641796]).

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CD20-targeting rituximab antibody is the standard-of-care for non-Hodgkin’s lymphoma (NHL). Recent clinical evidence suggests that high serum levels of the tumor-produced MUC16/CA125 protein has a negative impact on the efficacy of rituximab. To counteract the effects of CA125 binding to rituximab and reducing its tumor cell killing activity, Navrogen has generated a rituximab variant (NAV-006) using its BRITE proprietary technology. Navrogen will present data showing NAV-006’s superior efficacy over rituximab in animal models of human NHL. Navrogen’s screening technology has also found that CA125 inhibits other regulatory approved canonical and bispecific antibodies targeting CD19 and CD20 in relapsed/refractory NHL, underscoring a broader impact that CA125 has on biological drugs. "We are committed to combat cancers where humoral immunity is suppressed by CA125 and by other tumor-produced factors", said Dr. Luigi Grasso, Navrogen’s Chief Scientific Officer. "Our BRITE-optimized NAV-006 offers a new therapeutic modality to treat lymphoma patients with high levels of CA125 in relapsed/refractory disease".

Navrogen will also present the Humoral Immuno-Oncology (HIO) technology that has uncovered the tumor-produced protein ICAM-1, which binds to IgG1-type antibodies and inhibits their immune effector activity. "In addition to its immunosuppressive effects, we have found that membrane-bound ICAM-1 can reduce internalization of antibody-drug conjugates and their efficacy", continued Dr. Grasso. "We have engineered a trastuzumab-drug conjugate variant with superior cytotoxicity against ICAM-1 positive cancer cells. We are now building a portfolio of enhanced ADCs using this platform to advance internal as well as partnered ADC programs".

On April 4, 2024 ProfoundBio, a clinical-stage biotechnology company dedicated to developing novel antibody-drug conjugate (ADC) therapies for patients with cancer, reported its participation at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place from April 5-10 in San Diego, California (Press release, ProfoundBio, APR 4, 2024, View Source [SID1234641795]). ProfoundBio will showcase its innovative ADC programs through an oral presentation on its EGFR- and cMET-dual targeting ADC PRO1286, a poster presentation detailing preclinical data of a SLITRK6-directed ADC PRO1106, and a late-breaking poster presentation on a CD98-directed ADC developed in partnership with Huahui Health, a clinical-stage biotechnology company.

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"We are pleased to share our latest research at the AACR (Free AACR Whitepaper) Meeting this year," stated Zhu Chen, Ph.D., Chief Scientific Officer of ProfoundBio. "These presentations underscore our commitment to leveraging our proprietary ADC platforms to target some of the most challenging cancers. With PRO1286, PRO1106, and our CD98-directed ADC, we are aiming to provide patients with more effective and tolerable treatment options, and look forward to sharing the latest findings with the scientific community."

Key Presentations at AACR (Free AACR Whitepaper) 2024

Abstract #

Presentation Title

Date/Time

Session Track

Presenter(s)

2050

Preclinical characterization
of PRO1106, a novel and
promising SLITRK6-directed
sesutecan ADC

April 8,
2024,
9:00 AM –
12:30 PM

Poster Session,
Experimental and
Molecular
Therapeutics

Zhu Chen,
ProfoundBio

6580

A novel EGFR x cMET
bispecific ADC PRO1286
demonstrated broad
antitumor activity and
promising tolerability in
preclinical models

April 9,
2024,
3:05 PM –
3:20 PM

Minisymposium,
Experimental and
Molecular
Therapeutics,
Chemistry

Zhu Chen,
ProfoundBio

LB425

A tumor microenvironment –
targeting CD98-directed ADC
confers robust anti-tumor
activity in multiple cancers
with favorable
pharmacokinetics and safety
profiles in preclinical models

April 10,
2024,
9:00 AM –
12:30 PM

Late-Breaking
Poster Session,
Experimental and
Molecular
Therapeutics

Bin Chen,
Huahui Health

Zhu Chen,
ProfoundBio

About ProfoundBio’s ADC Programs

FRα-Targeted ADC: Rinatabart sesutecan (Rina-S, PRO1184)

Rina-S is a FRα-targeted ADC being developed as a novel treatment option for patients with ovarian and endometrial cancer, and other FRα-expressing cancers. Rina-S is comprised of a FRα-directed antibody conjugated to sesutecan, ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, at a homogeneous drug-to-antibody ratio (DAR) of 8. Exatecan is a potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect. The linker component of sesutecan is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of exatecan, enabling high DAR and efficient delivery of the exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC. Rina-S is currently being evaluated in a Phase 1/2 clinical trial (NCT05579366) and has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer.

CD70-Targeted ADC: PRO1160

PRO1160 is an ADC consisting of a CD70-targeted antibody conjugated to ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, sesutecan. CD70 is a protein expressed on both solid tumors and hematological malignancies including renal cell carcinoma, nasopharyngeal carcinoma, and non-Hodgkin lymphoma, yet is largely absent in normal tissues. With preclinical results showcasing encouraging pharmacokinetics, efficacy, and tolerability, PRO1160 is emerging as a potential advancement in the treatment of these cancers and is currently being evaluated in a Phase 1/2 clinical trial (NCT05721222).

PTK7-Targeted ADC: PRO1107

PRO1107 is an ADC consisting of a 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 with multiple marketed vedotin ADCs at a DAR of 4. The linker component of LD343 is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of MMAE, enabling high DAR and efficient delivery of the MMAE payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC. PRO1107 is currently being evaluated in a Phase 1/2 clinical trial (NCT06171789).

Bispecific ADC: PRO1286

PRO1286 is a novel EGFR- and cMET-dual targeting ADC that has the potential to treat a broad range of tumors. PRO1286 is built on the clinically validated sesutecan platform and is anticipated to enter the clinic in 2024.

On April 4, 2024 Biognosys, a global leader in mass spectrometry-based proteomics, and Alamar Biosciences, Inc., a company powering precision proteomics to enable the earliest detection of disease, reported a strategic partnership aimed at advancing scientific discovery in the field of biofluid proteomics biomarkers (Press release, Biognosys, APR 4, 2024, View Source [SID1234641793]). This collaboration brings together Biognosys’ expertise in unbiased discovery through data independent acquisition mass spectrometry (DIA-MS) and Alamar’s cutting-edge immunoassays. This integrated approach enhances our understanding of biomarkers by combining deep unbiased DIA-MS discovery proteomics with highly specific and ultra-sensitive mid- and high-plex NULISA assays for low-abundance proteins such as cytokines, chemokines and important disease protein biomarkers from plasma.

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In the Industry Spotlight Theater session hosted by Alamar at the American Society for Cancer Research (AACR) (Free AACR Whitepaper) 2024 Annual Meeting in San Diego on April 9 at 12:30 pm PT, the companies will jointly present data from a collaborative study focused on Non-Small Cell Lung Cancer (NSCLC). In this study, plasma samples from a cohort of NSCLC patients were analyzed using both the Biognosys TrueDiscovery unbiased discovery platform and Alamar’s NULISAseq Inflammation Panel 250. The findings demonstrate the feasibility of integrated analysis and highlight the complementary insights derived from mass spectrometry and affinity-based assays in plasma.

Building upon this successful proof-of-concept study, Biognosys and Alamar are planning to further collaborate both commercially and scientifically as part of their strategic partnership.

NULISA Assay Services: Biognosys will offer NULISA assays from its state-of-the-art facility in Switzerland for previously hard to measure cytokines, chemokines, as well as other important disease specific markers from plasma and biofluids. These ultra-high sensitivity assays enable precise quantification of low abundance proteins, providing researchers with valuable insights into complex biological processes. They complement unbiased DIA-MS analysis of thousands of plasma proteins to elucidate systemic host response, and other inflammation or disease-related protein-fold changes.

Research Collaboration: Biognosys and Alamar will embark on a joint research initiative to explore plasma biology. By leveraging Biognosys’ unbiased discovery methods alongside Alamar’s ultra-high sensitivity assays, the teams seek to unravel biological disease mechanisms by providing a more complete picture of the plasma proteome, enabling for the first time the coverage of essentially the complete dynamic range of protein abundance in plasma.
Oliver Rinner, Ph.D., Founder and CEO of Biognosys, expressed enthusiasm about the collaboration: "We are excited to join forces with Alamar to advance proteomics research. Our combined efforts will pave the way for breakthroughs in plasma biology by analyzing in an unbiased way more than 5,000 proteins together with panels of hundreds of well characterized cytokines and other high value low abundance proteins using highly specific NULISA assays. With this approach we are aiming to cover the whole dynamic range of plasma proteins."

"We are thrilled to partner with Biognosys to provide the research community with expanded access to proteomic insights from discovery through to clinical research," said Yuling Luo, Ph.D., Chairman, Founder and CEO of Alamar. "Biognosys is a leading provider of advanced mass spec proteomics services to researchers around the world, and we look forward to adding the highest sensitivity high-multiplex immunoassays to their plasma proteomics offering."

This partnership underscores the commitment of both companies to scientific excellence and their shared vision of advancing precision medicine through innovative technologies.

On April 4, 2024 Astrazeneca reported that positive high-level results of the ADRIATIC Phase III trial showed Imfinzi (durvalumab) demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with limited-stage small cell lung cancer (LS-SCLC) who had not progressed following concurrent chemoradiotherapy (cCRT) compared to placebo after cCRT (Press release, AstraZeneca, APR 4, 2024, View Source [SID1234641792]).

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Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy and radiotherapy in LS-SCLC patients.1,2 The prognosis is particularly poor for LS-SCLC, as only 15-30% of these patients will be alive five years after diagnosis.3

Suresh Senan, PhD, Professor of Clinical Experimental Radiotherapy at the Amsterdam University Medical Center, The Netherlands, and principal investigator in the trial said: "Many patients treated for limited-stage small cell lung cancer face disease recurrence and the standard of care has remained unchanged for decades. ADRIATIC is the first global Phase III immunotherapy trial to deliver significant, clinically meaningful improvement in survival in this setting, marking a breakthrough for patients with this devastating disease."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These exciting results build on the transformative efficacy of Imfinzi in extensive-stage small cell lung cancer and demonstrate the potential to bring a curative-intent immunotherapy treatment to this earlier-stage setting of small cell lung cancer for the first time. These data, together with the PACIFIC data in unresectable, Stage III non-small cell lung cancer, underscore the pioneering role of Imfinzi in the treatment of early lung cancer following chemoradiotherapy."

The safety profile for Imfinzi was consistent with its known profile, and no new safety signals were identified.

These data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

The second experimental arm testing the efficacy of Imjudo (tremelimumab) added to Imfinzi as a secondary endpoint remains blinded and will continue to the next planned analysis.

Imfinzi is approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage SCLC (ES-SCLC) based on the CASPIAN Phase III trial. Imfinzi is also the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after CRT based on the PACIFIC Phase III trial.

Notes:

Small cell lung cancer
Lung cancer is the leading cause of cancer death among men and women and accounts for about one-fifth of all cancer deaths.4 Lung cancer is broadly split into NSCLC and SCLC, with about 15% of cases classified as SCLC.5

LS-SCLC (Stage I-III) is classified as SCLC that is generally only in one lung or one side of the chest.6 LS-SCLC accounts for approximately 30% of SCLC diagnoses and the prognosis remains poor despite curative-intent treatment with standard-of-care cCRT.7

ADRIATIC
The ADRIATIC trial is a randomised, double-blind, placebo-controlled, multi-centre global Phase III trial evaluating Imfinzi monotherapy and Imfinzi plus Imjudo versus placebo in the treatment of 730 patients with LS-SCLC who had not progressed following cCRT. In the experimental arms, patients were randomised to receive a 1500mg fixed dose of Imfinzi with or without Imjudo 75mg every four weeks for up to four doses/cycles each, followed by Imfinzi every four weeks for up to 24 months.

The dual primary endpoints are PFS and OS for Imfinzi monotherapy versus placebo. Key secondary endpoints included OS and PFS for Imfinzi plus Imjudo versus placebo, safety and quality of life measures. The trial includes 164 centres in 19 countries across North and South America, Europe and Asia.

Imfinzi 
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, Imfinzi is currently approved in a number of countries in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC.

Imfinzi is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumours.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

In addition to its approved indications in combination with Imfinzi in liver and lung cancers, the combination of Imjudo and Imfinzi is being evaluated across multiple tumour types including locoregional HCC (EMERALD-3) and bladder cancer (VOLGA and NILE).