On April 8, 2024 EpiBiologics, a preclinical stage company advancing new bispecific antibody therapeutics for extracellular protein degradation, reported on its EpiTAC protein degraders in oncology demonstrating robust in vivo anti-tumor activity and survival benefit (Press release, EpiBiologics, APR 8, 2024, View Source [SID1234641911]). EpiTAC bispecific antibodies leverage cell-surface degrader receptors enriched in disease tissue to selectively degrade membrane and extracellular targets and address significant unmet needs.

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These data are being presented this morning at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in poster presentation #1866, "Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models" with Jon Sitrin, Ph.D., Head of Translational Science for EpiBiologics as lead author.

Current cancer treatments targeting EGFR often yield limited benefits due to target-related toxicities and reduced effectiveness in patients with acquired resistance. Recognizing the importance of improving therapeutic outcomes, EpiBiologics tested the efficacy of its novel EpiTACS on this oncogenic driver.

"Our proof-of-concept data demonstrate that EpiTAC activity is greater than standard of care in multiple preclinical tumor models. EpiTAC degradation of EGFR is mutation-independent and can overcome resistance mechanisms. These data motivate us to develop new and clinically meaningful therapies," said Shyra Gardai, Ph.D., Chief Scientific Officer of EpiBiologics.

Poster Presentation Highlights

EpiTACs are bispecific antibodies with a target binding arm and degrader binding arm that together localize degradation of extracellular and membrane targets to disease tissue, sparing normal tissue and increasing efficacy
Novel EpiTACs were rapidly selected and tested using the EpiAtlas of 270+ tumor- and tissue-specific degraders, including transmembrane E3 ubiquitin ligases, chemokine/cytokine receptors and tissue-enriched internalizing receptors
EpiTACs drove robust in vitro tumoricidal activity in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) models, independent of KRAS or EGFR mutational status
In vivo tumor models demonstrated EpiTACs degraded mutant EGFR and disrupts downstream signaling, suppressing tumor growth and increasing survival beyond osimertinib standard of care
"We believe EpiTACs are a promising new modality, especially for difficult-to-drug targets," said Ann Lee-Karlon, Ph.D., President and CEO of EpiBiologics. "Our modular bispecific antibodies coupled with our EpiAtlas allow us to rapidly screen and manufacture EpiTACs that drive deep anti-tumor responses. We’re committed to advancing EpiTACs for diverse targets in oncology and other disease areas as we move quickly toward the clinic."

On April 8, 2024 AbCellera (Nasdaq: ABCL) reported new data on its T-cell engager (TCE) programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)Ⓡ (AACR) (Free AACR Whitepaper) Annual Meeting 2024 at the San Diego Convention Center, with three posters being presented on April 8 and one on April 9. Together, AbCellera’s data demonstrate that it is well-positioned to advance TCEs as a drug class by widening the therapeutic window, enhancing potency, and broadening the accessible target space (Press release, AbCellera, APR 8, 2024, View Source [SID1234641910]).

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"TCEs are among the most promising new modalities in cancer therapy, but limitations in efficacy and safety have been barriers to realizing their potential for solid tumor indications," said Bo Barnhart, Ph.D., VP, Translational Research at AbCellera. "Our data illustrate that we can repeatedly generate TCEs that maximize tumor-cell killing without inducing excessive cytokine release. Reducing the risk associated with CD3 engagement could improve efficacy both by widening the therapeutic window and by creating opportunities to further enhance potency through co-stimulatory modalities."

AbCellera’s poster presentations, which are available for viewing here, describe how AbCellera is:

Widening the therapeutic window: AbCellera’s data describe the generation of TCEs for three solid tumor targets, PSMA, B7-H4, and 5T4, with functional profiles that are differentiated from clinical benchmarks. These molecules were engineered using a specific set of rare CD3-binding antibodies that consistently show potent tumor-cell killing and low cytokine release across multiple targets, demonstrating their potential to expand the therapeutic window across solid tumor indications.

Enhancing potency: TCEs that engage the CD28 costimulatory receptor can enhance T-cell activation, proliferation, and anti-tumor activities, particularly in solid tumors. The data show that AbCellera’s IgG and heavy chain-only CD28-binding antibodies do not display superagonist activity — a property associated with toxicity. Integrating costimulatory building blocks into AbCellera’s TCE repertoire may enable development of molecules with enhanced potency for difficult-to-treat cancers.

Broadening the accessible target space: The target repertoire for TCEs has been restricted to proteins expressed on the surface of cancer cells. Intracellular peptides displayed on MHC class I (pMHCs) would greatly expand the target pool for TCEs. However, development of TCEs against pMHCs has been limited due to the high degree of target specificity required. Data illustrate how AbCellera is unlocking this target class by generating molecules with high specificity for MAGE-A4-pMHC, which showed little to no binding to hundreds of off-target pMHCs.

"Our platform for creating precision TCEs to address indications in cancer and autoimmunity provides a strong foundation for both internal programs and strategic partnerships," said Murray McCutcheon, Ph.D., SVP, Partnering at AbCellera. "We look forward to advancing these programs with the aim of delivering powerful new medicines for patients."

On April 8, 2024 PanTher Therapeutics ("PanTher" or the "Company"), a clinical-stage oncology company developing high-dose, long lasting, localized treatments for cancer, reported positive data from a first-in-human study of PTM-101, a highly potent chemotherapeutic agent (paclitaxel) combined with an absorbable polymer formulated as a flexible film, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10th in San Diego (Press release, PanTher Therapeutics, APR 8, 2024, View Source [SID1234641909]).

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This first-in-human study enrolled three patients at a single center in Australia to assess the safety and surgical feasibility of a single, low-dose treatment of PTM-101. PTM-101 was placed directly onto the pancreas, overlying the location of the tumor using standard laparoscopic equipment as part of a disease staging assessment. Once in place over the tumor site, PTM-101 locally delivered a sustained dose of the chemotherapeutic agent over four weeks. Approximately three weeks after placement of PTM-101, all participants began standard of care therapy, which included treatment with mFOLFIRINOX.

Results of the clinical trial demonstrated that PTM-101 reduced the size of pancreatic tumors in all three patients. During the 24 weeks of the prospective phase of the study, the reduction in tumor thickness beneath PTM-101 ranged from 16% to 26%. Two patients had a significant reduction in overall tumor volume (40% and 70%). PTM-101 was also shown to have a favorable safety profile, as it was well-tolerated with no peritonitis, pancreatitis, infection, or hematological toxicity. The chemotherapeutic agent remained localized to the pancreas in all patients, with no detection of systemic paclitaxel at any timepoint.

"Historically, there have been significant clinical challenges realizing the benefits of chemotherapeutics when they are administered systemically. Maintaining a high drug concentration is limited by the route of administration as well as toxicity, which negatively impacts the effectiveness of the drug," said Laura Indolfi, PhD, Chief Executive Officer, and co-founder of PanTher Therapeutics. "We are encouraged by the early clinical data of PTM-101 in patients with locally advanced pancreatic cancer, further validating the potential of our Sagittari platform to deliver high-concentrations of drug directly to the site of a tumor for an extended period of time, without commonly observed undesired side effects."

"Use of PTM-101 to locally administer a highly potent drug, without the limitations from systemic safety and tolerability issues, offers the potential to facilitate significant improvement in patient outcomes, which is clearly needed in the treatment of pancreatic cancer," said Charles Pilgrim, MD, PhD, Associate Professor of Surgery at the Alfred Central Clinical School at Monash University, and principal investigator of the PTM-101 phase 1 clinical trial. "The ability of PTM-101, in combination with standard of care chemotherapy, to shrink pancreatic tumors as observed in this initial study is promising. The prognosis for patients with pancreatic cancer can be particularly devastating, as it is often detected at an advanced stage, at which point there are limited treatment options. Given the trajectory for this cancer, I am very encouraged by the results from the clinical trial of PTM-101 in locally advanced cases and the ease of integrating the treatment into current clinical practice and standard laparoscopic procedures."

PanTher presented a second poster at AACR (Free AACR Whitepaper) describing the non-clinical development of PTM-101.

Both posters are available on the PanTher Therapeutics website.

On April 8, 2024 Exai Bio reported new breast cancer data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2024 annual meeting. In a new study, Exai’s novel RNA- and AI-based liquid biopsy platform demonstrated stage I breast cancer detection sensitivity of 90% and ductal carcinoma in situ (DCIS) sensitivity of 88%, both at 90% specificity (Press release, Exai Bio, APR 8, 2024, View Source [SID1234641908]). In addition, the study showed the platform’s unique capability to distinguish low grade, less aggressive DCIS from invasive breast cancer with 87% sensitivity, at 90% specificity using a standard blood sample. More than 55,000 women were diagnosed with DCIS in 2023 in the United States. The current standard of care treatment for the majority of these women is invasive treatment despite the fact that an estimated 60–80% of cases do not progress to cancer. These early data suggest a blood test can become an effective way to not only detect early-stage breast cancer but also monitor low grade DCIS so that more women can have the option of avoiding aggressive or unnecessary treatment.

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"These results further validate the power of Exai’s novel RNA- and AI-based liquid biopsy platform to detect breast cancer at its earliest stages with high sensitivity, overcoming the limitations of DNA-based approaches"

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"These results further validate the power of Exai’s novel RNA- and AI-based liquid biopsy platform to detect breast cancer at its earliest stages with high sensitivity, overcoming the limitations of DNA-based approaches," stated Pat Arensdorf, Chief Executive Officer of Exai Bio. "In addition to strong early detection performance, this study also demonstrated for the first time that our platform can distinguish low grade DCIS from invasive breast cancer with high accuracy. These findings are very promising and indicate the potential for a blood-based test to monitor women who are diagnosed with low grade DCIS."

In addition, Exai announced results from a new breast cancer molecular residual disease (MRD) study conducted in collaboration with the University of Kansas Medical Center. The study demonstrated that Exai’s tumor-naive platform — which does not require sequencing the tumor tissue — can accurately predict survival in the post-adjuvant setting for patients with triple negative breast cancer. These results suggest the potential for Exai’s platform to aid in tailoring adjuvant treatment for individual triple negative breast cancer patients.

Exai’s platform uses RNA sequencing to identify a novel category of cancer-associated, small non-coding RNAs, termed orphan non-coding RNAs (oncRNAs). oncRNAs are actively secreted from living cancer cells and are stable and abundant in the blood of cancer patients. Exai has created a catalog of hundreds of thousands of oncRNAs and thousands of patient oncRNA profiles, spanning all major cancer types. When combined with proprietary artificial intelligence technology, the Exai platform has multiple technical and operational advantages over tests that utilize circulating tumor DNA. These include superior sensitivity and specificity, as well as the ability to reveal dynamic changes in the biology of a patient’s tumor over time. Exai’s universal platform can be used across multiple cancer care settings such as screening and early detection, monitoring, molecular residual disease, and therapy selection.

AACR Presentation Details

Title: Beyond detection: AI-based classification of breast cancer invasiveness using cell-free orphan non-coding RNAs

Abstract Number: 3678

Session: Clinical Research Excluding Trial, Circulating Nucleic Acids 3, Poster Section 41

Authors: M. Karimzadeh, T. Cavazos, N. Chen, N. Tbeileh, D. Siegel, A. Momen-Roknabadi, J. Yen, J. Ku, S. Chen, D. Corti, A. Huang, D. Nguyen, R. Hanna, T. Lam, S. Kilinc, P. Murzynowski, J. Wang, X. Zhao, A. Pohl, B. Behsaz, H. Li, L. Fish, K. Chau, L. Van’t Veer, L. Esserman, P. Arensdorf, H. Goodarzi, F. Hormozdiari, B. Alipanahi

Title: Orphan non-coding RNA (oncRNA) liquid biopsy assay is prognostic for survival in patients with triple-negative breast cancer (TNBC) and residual disease

Abstract Number: 5215

Session: Clinical Research Excluding Trial, Prognostic Biomarkers 1, Poster Section 46

Authors: R. Yoder, J. Yen, M. Karimzadeh, J. Staley, I. Fernandez, A. Heinrich, F. Hormozdiari, J. Gregg, A. Godwin, I. Acerbi, R. Trivedi, B. Alipanahi, S. Stecklein, P. Sharma

On April 8, 2024 Tubulis reported comprehensive preclinical data on its two lead antibody-drug conjugate (ADC) candidates TUB-030 and TUB-040 at this year’s Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in San Diego (Press release, Tubulis, APR 8, 2024, View Source [SID1234641907]). The poster presentations contained preclinical data, highlighting the ability of the two next-generation Tubutecan ADCs to create effective and durable responses even in low target-expressing tumor mouse models. Tubulis is leveraging a proprietary suite of platform technologies to build a pipeline of uniquely matched ADC candidates that combine the right targeting molecule, conjugation chemistry and payload to deliver the true therapeutic value of the ADC approach. The company’s lead candidates, both targeting solid tumor indications, are in late-stage preclinical testing, with TUB-040 ready for clinical evaluation.

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"These compelling preclinical data sets for both of our lead ADC candidates, TUB-030 and TUB-040, support how our proprietary platforms create ADCs with unique biophysical properties allowing for continued and durable on-tumor delivery of the payload. The in vivo studies have demonstrated that both candidates show strong, long-lasting anti-tumor activity, even at lower expression levels of the respective targets," said Jonas Helma-Smets, Chief Scientific Officer of Tubulis. "Our ADCs are highly differentiated compared to other ADCs on the market and we look forward to translating these findings into the clinic with the goal of improving overall survival and duration of response in patients across a broad range of solid tumors. Starting with TUB-040, we aim to initiate first clinical trials this year and thereby provide clinical proof-of-concept for our next-generation ADCs and our differentiated platform approach to ADC design."

Both ADC candidates are comprised of a humanized, target-specific, Fc-silenced IgG1 antibody conjugated to the topoisomerase-1 inhibitor Exatecan with Tubulis’ Tubutecan linker-payload platform via the proprietary P5 conjugation platform, resulting in highly stable and homogenous drug-to-antibody-ratio of 8 (DAR8) ADCs. Compared to maleimide-conjugated ADCs, TUB-030 and TUB-040 both showed superior stability and minimal loss of linker-payload conjugation.

Highlights of Tubulis’ preclinical data presented at AACR (Free AACR Whitepaper) 2024:

TUB-040

TUB-040 is built with novel Tubutecan linker-payload chemistry and superb biophysical properties, targeting Napi2b, a highly overexpressed antigen in ovarian cancer and lung adenocarcinoma
The ADC candidate is highly stable and highly inert in circulation, enabling powerful and continued on-tumor delivery of the payload, leading to complete eradication of tumors with a low dose single treatment in multiple ovarian cancer mouse models
Enabled by the differentiated Tubutecan linker-payload and strong bystander activity, TUB-040 showed significantly better durability of antitumor activity in preclinical models compared to lifastuzumab vedotin
In ovarian cancer and non-small-cell lung cancer (NSCLC) patient derived xenograft mouse models, treatment with TUB-040 led to robust long-lasting tumor regressions
Repeat-dose toxicology studies of TUB-040 in non-human primates demonstrated that TUB-040 was well tolerated with minor and reversible adverse effects
TUB-030

TUB-030 is built with novel Tubutecan linker-payload chemistry and superb biophysical properties, targeting 5T4, a tumor-associated antigen expressed in a broad range of solid tumors
The ADC candidate demonstrated target-specific cytotoxicity as well as strong bystander activity, facilitating the destruction of cells that do not express the target antigen but are in the direct vicinity of the targeted tumor cell, thereby broadening the effect of the ADC
A single treatment with TUB-030 was shown to eliminate tumors in a triple negative breast cancer mouse model, whereas PF06263507, a clinically tested comparator ADC led to re-growth of tumors.
In over 25 patient derived xenograft mouse models of various types of cancer, TUB-030 showed high efficacy rates even at low 5T4 expression levels and achieved long-lasting and durable anti-tumor activity
TUB-030 was well tolerated in non-human primates and showed highly restricted binding to normal fresh frozen human tissues
The full abstracts were published in an online-only proceedings supplement to the AACR (Free AACR Whitepaper) journal, Cancer Research in March and can be accessed here.