On April 17, 2023 PIC Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first-in-mechanism, first-in-class allosteric small molecule therapies targeting eIF4E, reported pre-clinical data today on the company’s advancing eIF4E program for breast cancer in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place in Orlando, FL (Press release, PIC Therapeutics, APR 17, 2023, View Source [SID1234630216]).

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Advanced or metastatic breast cancers represent a large patient population with limited long-term solutions that address both the heterogenous nature of resistant tumors and the aggressiveness of their proliferation. The aim of our therapies is to drive strong mechanistic responses, in a majority of breast cancer tumor subtypes, that induce a rapid commitment to cell death. To accomplish this, our approach addresses a key fundamental mechanism in protein translation at the convergence of many oncogenic signaling pathways through which resistance arises.

eIF4E is a key component of protein translation that often becomes dysregulated in breast cancer, supporting cell survival and metastasis alongside therapeutic resistance. PIC compound regulation of eIF4E induces rapid commitment to apoptosis and selective proteomic shifts that are consistent with canonical eIF4E regulation including cell cycle impacts, e.g. effects on cyclin family members and CDKs, DNA repair regulation and metabolic proteins. PIC Compounds also potently impact multiple clinical drivers for ER+ and Triple Negative Breast Cancers, which are evidenced by mRNA signatures that include changes consistent with proteomic impacts to key transcription factors.

Previous communications revealed our eIF4E regulators potently cause cell death in primary breast cancer organoid models, but spared models derived from healthy tissue. Expanding our efforts in this domain, the impact on normal immune cells was evaluated by exposing PBMCs, CD4+ T cells, and bone marrow mononuclear cells to our compounds. Our eIF4E regulators did not impair survival of these cells up to a maximum tested dose of 25 micromolar. Primary CD4+ T cells were also found to be functional in the presence of eIF4E regulators up to 5 micromolar, which included assessments of CD3/CD28 stimulated cytokine production and proliferative responses, highlighting its remarkable differentiated impact on normal cells compared to tumor cells.

"We continue to uncover interesting and distinctive preclinical data sets that underscore the potential for unique therapeutic advantages of allosterically regulating eIF4E, as a promising strategy for patients with various subtypes of breast cancer," said Kathy Bowdish, Ph.D., President and Chief Executive Officer of PIC Therapeutics.

Our findings suggest that allosteric regulation of eIF4E provides a unique and efficient way to address multiple resistance mechanisms while sparing normal immune cellular function. Our eIF4E regulators represent a potential beneficial therapeutic approach to address multiple resistant cancer patient populations and fulfill the promise of this elusive target.

Presentation details:

Title: eIF4E allosteric regulators cause rapid commitment to apoptosis in cancer cells while sparing immune cells

Session Category: Experimental and Molecular Therapeutics

Session Title: Novel Antitumor Agents 3

Session Date and Time: Monday April 17, 9:00 AM – 12:30 PM

Location: Section 17

Poster Board Number: 14

Abstract Number: 1624

On April 17, 2023 Lassen Therapeutics, a clinical-stage biotech company developing breakthrough antibody therapeutics as potential treatments for immuno-fibrotic diseases and cancer, reported that it will present new preclinical data demonstrating activity of its anti-interleukin-18 binding protein (IL-18BP) antibody and efficacy in combination with anti-PD-1 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, being held in Orlando, Florida (Press release, Lassen Therapeutics, APR 17, 2023, View Source [SID1234630215]). The poster presentation is part of the Immunomodulatory Agents and Interventions session which takes place today, Monday April 17th, from 9:00 AM to 12:30 PM ET.

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IL-18BP is a soluble inhibitory decoy receptor that binds to interleukin-18 (IL-18) and serves as a checkpoint to modulate and inhibit the potent proinflammatory effects of IL-18 on both the innate and adaptive immune system. IL-18 has demonstrated efficacy in certain tumor models; IL-18 clinical trials have not, however, shown efficacy of this treatment due to increased expression of IL-18BP with consequent inhibition of activity.

Lassen’s anti-IL18BP antibodies demonstrated anti-tumor efficacy in a mouse syngeneic tumor model in combination with IL-18, anti-PD-1, and anti-PD-1 plus IL-18. The antibodies have been shown to induce potent stimulation of interferon gamma and other proinflammatory cytokines and chemokines in vitro and in vivo.

"We have identified high affinity, high potency anti-IL-18BP antibodies capable of disrupting and inhibiting the formation of IL-18BP/IL-18 complexes to liberate IL-18," said David King, PhD, Chief Scientific Officer of Lassen. "Our data suggest that inhibition of IL-18BP/IL-18 binding may prove efficacious in the treatment of cancers by increasing the immunostimulatory effects of IL-18 in tumors.

On April 17, 2023 AbCellera (Nasdaq: ABCL) reported new data on its T-cell engager (TCE) platform in two poster presentations at the American Society for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, which is being held at the Orange County Convention Center in Orlando, Florida, from April 14 to 19, 2023 (Press release, AbCellera, APR 17, 2023, View Source [SID1234630214]). AbCellera debuted its TCE platform at AACR (Free AACR Whitepaper) 2022 with data describing the diversity of its CD3-binding antibodies. Presentations at AACR (Free AACR Whitepaper) 2023 illustrated how AbCellera streamlines the development of TCEs with optimal functional properties for diverse tumor targets.

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"T-cell engagers are amongst the most promising new modalities in cancer therapy. The robust characterization of our novel CD3-binding antibodies in both mono- and bispecific formats illustrates that we can engineer optimal TCEs by fine-tuning tumor cell killing and cytokine release," says Bo Barnhart, Ph.D., VP, Translational Research at AbCellera. "Combined with our ability to discover antibodies against some of the most challenging cancer targets, our engine can enable the development of custom-built TCEs for a wide range of cancers."

First, AbCellera demonstrated that its panel of novel, fully human CD3-binding antibodies can build optimized TCEs that have functional profiles superior to benchmark molecules. The presentation included:

A comprehensive data package on a panel of CD3-binding antibodies, including binding and functional comparisons to molecules commonly used for TCE development.
Two proof-of-concept studies in which novel CD3-binding antibodies were used to engineer TCEs for different tumor targets. The resulting TCEs included bispecific antibodies with high potencies and low cytokine release in in vitro assays. Differences in T-cell function across tumor targets emphasized the importance of selecting the right CD3- and tumor-binding antibodies for an optimal TCE. These data demonstrate how AbCellera’s novel CD3-binding antibodies enable development of custom-built TCEs for different tumor targets.
In another poster, AbCellera described the discovery of highly specific and developable antibodies against a validated peptide-major histocompatibility complex (pMHC) tumor target. Melanoma-associated antigen 4 (MAGE-A4) is a tumor-specific antigen expressed by many solid tumors, but not by most healthy tissue. Effectively targeting pMHCs presenting tumor-specific antigens with TCEs could unlock tumor targets that are expressed inside the cell, which are generally inaccessible with this modality. AbCellera used its antibody discovery and development engine to generate antibodies that bind to MAGE-A4-pMHC. Strategic selection and pairing of AbCellera’s target- and CD3-binding antibodies has the potential to power the discovery of optimal TCEs targeting MAGE-A4-pMHC.

"In late 2021, we recognized a gap that was preventing powerful TCE cancer treatments from making it to patients and felt confident that our antibody discovery and development engine could provide the solution," said Murray McCutcheon, Ph.D., Senior VP, Partnering. "In 18 months, we have developed a TCE discovery platform and are leveraging the extensive datasets we’ve generated to custom-build TCEs and help bring better cancer treatments to patients faster."

AbCellera’s poster presentations are available for viewing here.

About T-Cell Engagers

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

On April 17, 2023 Halda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTACTM (Regulated Induced Proximity TArgeting Chimeras) therapeutics, reported a poster presentation for its lead RIPTAC therapeutic program for prostate cancer at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held in Orlando, Florida, from April 14-19, 2023 (Press release, Halda Therapeutics, APR 17, 2023, View Source [SID1234630213]). The preclinical data showed oral efficacy of the RIPTAC therapeutics as a monotherapy and demonstrated anti-tumor activity superior to the standard of care agent in prostate cancer, enzalutamide. Combination therapy with PARP inhibitors is also being explored and RIPTAC therapeutics may have a complementary mechanism.

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"Our presentation at AACR (Free AACR Whitepaper) is an exciting opportunity to share the growing body of evidence demonstrating the anti-tumor efficacy of the "hold and kill" mechanism of RIPTAC therapeutics which can be applied to address cancers in early or later-line therapy," said Kat Kayser-Bricker, PhD, Chief Scientific Officer of Halda Therapeutics. "These preclinical efficacy results of RIPTAC therapeutics targeting prostate cancer highlight the promise of a novel approach to overcome bypass mechanisms of resistance that evolve during cancer therapy, which is a common limitation of today’s precision oncology medicines."

The preclinical data describe the anti-tumor activity of prostate cancer RIPTAC therapeutics, novel orally bioavailable heterobifunctional small molecules, that use a unique "hold and kill" mechanism resulting in selective cancer cell killing by bringing together two proteins: the tumor-specific protein androgen receptor (AR) and an essential protein involved in transcription regulation. A trimeric complex is formed by the prostate cancer RIPTAC therapeutic and the two proteins which drives the formation of new protein-protein interactions; the resultant trimeric species thereby abrogates the function of the essential protein within AR-expressing prostate cancer cells, leading to selective cancer cell death.

The poster presentation, with lead author Xinheng Yu, PhD, Research Investigator at Halda, is entitled "Prostate Cancer RIPTACTM Therapeutics Demonstrate Activity in Preclinical Models of Enzalutamide-Resistant Prostate Cancer," and includes the following results:

In prostate cancer cells, the RIPTAC therapeutics demonstrated the formation of trimeric complexes with AR (and clinically relevant AR mutants) and a protein with essential function involved in transcription regulation.
In castrated mice bearing VCaP xenografts, multiple RIPTAC therapeutics demonstrated superior oral efficacy in vivo compared with enzalutamide, the current standard of care agent for prostate cancer.
RIPTAC therapeutics targeting prostate cancer downregulated genes involved in homologous recombination repair, inducing BRCAness. PARP inhibitors can induce synthetic lethality under these conditions, and combination therapy will be explored.
The design of the RIPTAC therapeutics targeting prostate cancer achieved desired anti-tumor activity and pharmacology through optimized trimeric complex formation, AR-selective cell killing, and oral bioavailability.
The poster presentation can be found on Halda’s website here.

About Prostate Cancer and mCRPC

Prostate cancer is the most common non-skin cancer in men. In the U.S., 1 in 8 men will be diagnosed with prostate cancer in his lifetime.1 Prostate cancer depends on the androgen receptor (AR), a transcription factor critical for prostate cancer growth and progression. Treatment initially relies on androgen deprivation therapy, as well as AR signaling inhibitors (ARSIs). However, resistance to antiandrogen interventions eventually emerges, and is driven by many heterogenous bypass mechanisms including genomic alterations in AR. The long-term prognosis for patients with metastatic castration resistant prostate cancer (mCRPC) is poor, with a relatively short overall survival. In the mCRPC form of the disease, more than 80% of patients harbor amplifications of the AR gene or the upstream enhancer region of DNA.2 AR remains expressed in tumors even if they are no longer AR dependent, dramatically reducing effectiveness of ARSIs, thus representing a vast unmet need.

On April 17, 2023 Avistone Biotechnology ("Avistone" or "the Company"), a clinical-stage biotechnology company focused on precision oncology therapeutics, reported interim results from its ongoing phase 1 study on PLB1004 (Press release, Avistone Pharmaceuticals, APR 17, 2023, View Source [SID1234630212]). The data were presented today (CT102) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, Florida USA.

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PLB1004, a novel mono-anilino-pyrimidine small molecule inhibitor of EGFR, potently and irreversibly targets exon 20 insertion. The molecule also potently targets classical EGFR mutations ExDel19, L858R and T790M with a high degree of selectivity over wild-type EGFR.

The study is a multi-center, open-label, dose escalation and expansion study conducted entirely in China, to assess the safety, tolerability, pharmacokinetics, and anti-tumor effect of PLB1004, administered orally, in patients with advanced non-small cell lung cancer. The primary objective of the study is to assess the safety profile of PLB1004 and determine the RP2D of the molecule.

At the cutoff date for these interim results, July 31, 2022, a total of 65 patients (32 in escalation and 33 in expansion) had received treatment with PLB1004. Dose escalation ranged from a starting dose of 10 mg QD to a top dose of 480 mg QD in 11 cohorts of patients. As of July 31, 2022, dose expansion occurred at two dose levels, 320 mg QD and 400 mg QD. The median age of the patients is 58 years old (range 31 to 77). Most patients are women (60%) with adenocarcinoma (95%) and good performance status (ECOG 0-1 in 98%). The most frequent treatment related adverse events included diarrhea in 75% of patients (19% Grade 3), rash in 60% of patients (11% Grade 3), mouth ulceration in 43% of patients (1.5% Grade 3), elevated serum creatinine in 43% of patients (2% Grade 3) and elevated aspartate aminotransferase in 41% of patients (3% Grade 3). No DLTs were observed at any dose level and thus an MTD was not determined during cycle 1 of drug administration. Beyond Cycle 1, at the highest dose levels, frequent dose interruptions and reductions due to toxicity were observed, and further dose escalation was not attempted above 480 mg QD. Across all dose groups, a total of 38 subjects had EGFR Ex20ins mutations, including 29 at doses ≥ 160 mg QD, among whom 26 completed at least 1 tumor assessment. In these 26 patients the confirmed best response rate was 57.7% (15/26) and the disease control rate (DCR) was 100% (26/26). Among the 26 patients (≥160mg QD dose level) with EGFR Ex20ins mutation who completed at least one tumor evaluation, 8 patients had brain metastases, and 3 of them had a PR (37.5%).

"PLB1004 appears to be safe and well-tolerated with promising anti-tumor activity in patients with NSCLC harboring EGFR exon 20 insertion mutations," said Jin-Ji Yang, M.D., Primary Investigator from Guangdong Provincial People’s Hospital.

"Avistone is a science-driven, innovative biotechnology company committed to the discovery and clinical development of first-in-class and best-in-class drugs," said Dr. Hepeng Shi, Chairman, CEO, and Founder of Avistone. "We are proud to share data at this year’s AACR (Free AACR Whitepaper) conference for PLB1004 which has best-in-class potential for patients with EGFR NSCLC. We are excited to present these additional data and to highlight the advancements we are achieving for patients with lung cancer."

Electronic copies of the poster presented at the AACR (Free AACR Whitepaper) annual meeting are available upon request.