On April 17, 2023 Boundless Bio, a clinical stage next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in oncogene amplified cancers, reported it will present at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, held in Orlando and virtually from April 14-19, 2023 (Press release, Boundless Bio, APR 17, 2023, View Source [SID1234630218]). The poster "Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition" is available for in-person presentation on April 17, 2023 at 9:00 a.m. – 12:30 p.m. ET.

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"We are excited to unveil CHK1 as the ecDNA-essential target for our first novel ecDNA-directed therapy (ecDTx)," said Christian Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. "Leveraging our proprietary ecDNA-centric research platform, Spyglass, we identified CHK1 as an essential regulator of replication stress associated with oncogene amplification on ecDNA, revealing a unique, druggable, and cancer-specific liability. Our research revealed that ecDNA-enabled cancers have an exquisite reliance on CHK1 to manage intrinsically elevated replication stress, and this important discovery has led to the development of the first ecDTx, BBI-355. BBI-355, a potentially best-in-class, oral, and selective CHK1 inhibitor, is the subject of a recently initiated first-in-human Phase 1/2 clinical study."

Patients with tumors that harbor oncogene amplification on ecDNA have poor prognosis and generally do not respond well to targeted therapies and possibly immunotherapies. Boundless Bio has previously presented the relationship between oncogene amplification on ecDNA and DNA replication stress, a known form of genomic instability that contributes to oncogenesis and tumor evolution. Today we present data showing that cancer cells with oncogenes amplified on ecDNA are hyper-reliant on CHK1 to survive and that inhibition of CHK1 in ecDNA-enabled cancer cells is synthetically lethal. Using our Spyglass platform, we identified CHK1 as an ecDNA essential drug target through a CRISPR genetic screen and further pharmacologically validated its essential role in multiple ecDNA model systems across various tumor types and oncogene drivers.

We designed BBI-355, an orally available, highly potent, and selective inhibitor of CHK1 to target this unique genetic susceptibility in ecDNA-bearing cancer cells. In January of this year, the FDA accepted our investigational new drug application to enable the BBI-355-101 Phase 1/2 clinical trial of BBI-355, which is now open for enrollment of patients with oncogene amplified solid tumors.

About Extrachromosomal DNA (ecDNA)

ecDNA are circular units of nuclear DNA that are physically distinct from chromosomes and are found only within cancer cells. ecDNA encode full length genes, including oncogenes and regulatory regions, are highly transcriptionally active, and lack centromeres. ecDNA replicate and express within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and gene copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells can increase or decrease copy number of select genes located on ecDNA to enable survival under selective pressures, including targeted therapy, chemotherapy, or radiation, thereby making ecDNA one of cancer’s primary mechanisms of growth and treatment resistance. ecDNA are not found in healthy cells but are present in many cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

About BBI-355

BBI-355 is a potentially best-in-class checkpoint kinase 1 (CHK1) inhibitor and the first ecDNA-directed therapy (ecDTx) being investigated to treat patients with oncogene amplified cancers. CHK1 is a master regulator of DNA replication stress (RS), which frequently arises from oncogene amplification on extrachromosomal DNA (ecDNA). Inhibition of CHK1 by BBI-355 is synthetic lethal in cancer cells with oncogene amplification on ecDNA due to their heightened RS. CHK1 was identified and validated as an ecDNA essential target via Boundless Bio’s proprietary Spyglass platform and led to the development of BBI-355, an orally available, potent, and selective inhibitor of CHK1. BBI-355 is currently being evaluated in a first-in-human trial designed to evaluate the safety, maximum tolerated dose, and recommended Phase 2 dose of BBI-355 as a single agent and in combination with select therapies in patients with locally advanced or metastatic solid tumors with oncogene amplifications.

On April 17, 2023 Strand Therapeutics, the programmable mRNA company developing curative therapies for cancer and other diseases, reported preclinical data from its programmable mRNA therapy STX-001, a multi-modal synthetic self-replicating mRNA technology that delivers a prolonged and locally-acting IL-12 cytokine to the tumor microenvironment (Press release, Strand Therapeutics, APR 17, 2023, View Source [SID1234630217]).

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Immunotherapy has revolutionized cancer treatment, but only a minority of patients experience durable clinical responses. One of the reasons for this limited efficacy is the failure of immune checkpoint inhibitors to sufficiently activate and recruit T cells into the tumor microenvironment.

STX-001, when delivered directly to the tumor, induces a highly immunogenic tumor cell death while the mRNA-encoded IL-12 payload promotes recruitment of effector T cells and NK cells into the tumor microenvironment. STX-001 shows promise as a new approach to improve the efficacy of current immunotherapies for solid tumors. STX-001’s self-replicating mRNA technology induces immunogenic tumor cell death and promotes recruitment of T cells and NK cells to the tumor microenvironment as well as their activation.

"Our programmable mRNA therapy STX-001 overcomes the limitations of current immunotherapy to improve clinical responses to solid tumors. The major breakthrough is that we’ve shown for the first time our therapy enables the delivery of therapeutic quantities of IL-12 with greater efficacy than conventional mRNA," said Tasuku Kitada, Ph.D., President and Head of R&D of Strand Therapeutics.

"This early data also shows that STX-001 induces durable anti-tumor responses and enhances efficacy when combined with PD-1/PD-L1 checkpoint inhibitors. STX-001 represents a promising new approach for the treatment of solid tumors, and we look forward to advancing this candidate into clinical trials later this year," said Prashant Nambiar, DVM, Ph.D., Senior Vice President, Research and Translational Development.

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.