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.

On April 17, 2023 GRAIL, LLC, a healthcare company whose mission is to detect cancer early when it can be cured, and AstraZeneca (LSE/STO/Nasdaq: AZN), reported new data from a study assessing the feasibility of a pan-hematologic malignancy classifier (pan-heme classifier) based on GRAIL’s methylation platform as a potential tumor-agnostic, plasma-based cell free DNA minimal residual disease (MRD) test (Press release, Grail, APR 17, 2023, View Source [SID1234630211]). The study showed that GRAIL’s methylation technology had a cancer detection rate of 92% in patients with relapsed or refractory disease across six hematological malignancies. The findings were reported during a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, held April 14-19.

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"Currently there is no standard method to detect residual cancer DNA in patients across multiple types of blood cancer. Following treatment, a small number of cancer cells can remain in the body, which don’t cause symptoms but could begin to multiply and cause relapse," said Jeffrey Venstrom, M.D., Chief Medical Officer at GRAIL. "A blood-based methylation test offers a potential solution to evaluate patients periodically with the goal of extending remission and survival."

Baseline blood samples were collected from patients with six subtypes of hematologic malignancies and tested with GRAIL’s assay to identify residual cancer using targeted methylation sequencing and advanced machine learning algorithms. The majority of samples (88%) were from relapsed or refractory blood cancers that were blindly tested retrospectively. The pan-heme classifier accurately detected cancer in 92% of the 428 samples tested (98% in chronic lymphocytic leukemia; >98% in multiple myeloma; >95% in non-Hodgkin lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma; and 87% in acute myeloid leukemia samples). Cancer was reproducibly detected in 89% (48 of 54) of cases where paired samples were taken prior to treatment, demonstrating high biological precision. Furthermore, serially diluted DLBCL and CLL patient plasma samples were spiked into healthy volunteer plasma samples to estimate an initial pan-heme classifier LOD of 10-3 – 10-4 methyl variant allele fraction (MVAF) with <2% false positive rate. The assay and pan-heme classifier is currently under improvement and optimization.

"The findings presented at AACR (Free AACR Whitepaper) support further development of a methylation-based pan- hematologic malignancy algorithm, which could help in standardizing a method of detecting residual cancer DNA in patients after they are treated for various types of blood cancers," said Daniel Auclair, Hematology R&D at AstraZeneca. "These data show that methylated DNA might be a good marker for detecting residual cancer across multiple hematological malignancies in post-treatment settings and warrants further study."

GRAIL previously announced a broad strategic collaboration with AstraZeneca to develop and commercialize companion diagnostic (CDx) assays for use with AstraZeneca’s therapies. The collaboration initially focused on developing companion diagnostic tests to identify patients with high-risk, early-stage disease.

On April 17, 2023 Data of InnoCare’s (HKEX: 09969; SSE: 688428) reported that its robust oncology pipelines were presented at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, InnoCare Pharma, APR 17, 2023, View Source [SID1234630210]).

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Oral Presentation:

ICP-490 is a highly potent and selective IKZF1/3 degrader with robust anti-tumor activities against multiple myeloma and non-Hodgkin’s lymphoma

Abstract Number: 3427

In various multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) tumor models, ICP-490 demonstrates superior tumor killing activities, including overcoming lenalidomide resistance. ICP-490 is now in phase I clinical trial.

Cell viability assays reveal robust in vitro efficacies of ICP-490 against various MM and NHL(including DLBCL) cell lines with nanomolar IC50. It also exhibits potent anti-proliferative activity in lenalidomide-resistant cell lines. In contrast to its tumor killing effect, ICP-490 shows no cytotoxicity against normal human cells. In vivo efficacy studies have further confirmed the effectiveness of ICP-490 against various MM and DLBCL xenografts.

The immune modulation activity of ICP-490 has also been illustrated in a combinatory treatment with monoclonal antibody, where low dose of ICP-490 leads to robust induction of IL-2 and granzyme B, and much improved efficacy of anti-CD38 mAbs in MM; in NHL, ICP-490 demonstrates synergistic tumor killing effects when combined with BTK inhibitor orelabrutinib.

ICP-490 has overall favorable pharmacokinetic parameters with high oral bioavailability.

Poster Presentation 1:

Combination of BTK inhibitor orelabrutinib, anti-CD19 antibody tafasitamab, and IMiD lenalidomide for the treatment of B cell malignancies

Abstract Number: 4013

R-CHOP has been widely recognized as effective first-line treatment for DLBCL. However, 30-50% of the patients are either refractory or eventually develop relapsed diseases (r/r DLBCL). Multiple clinical trials of orelabrutinib are being carried out for the treatment of DLBCL, including the first-line treatment of MCD subtype of DLBCL. An exploratory study to evaluate the safety and efficacy of orelabrutinib, tafasitamab and lenalidomide combinations in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) is ongoing.

The highly selective BTK inhibitor orelabrutinib is a superior combinatory partner with antibody therapeutics whose mechanism of action is highly dependent on ADCC. Orelabrutinib is a highly selective BTK inhibitor with no inhibition effect on T cells, which confers its ability to enhance or retain the ADCC activity of tafasitamab. Combination of orelabrutinib with tafasitamab and/or lenalidomide also leads to synergistic tumor lysis activity, with or without the presence of immune effector cells. Confirmation of the synergistic effects of orelabrutinib with tafasitamab and lenalidomide in various preclinical models has provided scientific rationales for testing the combinatory treatment in clinical studies.

Poster Presentation 2:

Preclinical development of SHP2 allosteric inhibitor ICP-189

Abstract Number: 4012

ICP-189 is a novel allosteric inhibitor of SHP2 with broad-spectrum anti-tumor activities as a single agent or in combination with other targeted or immune modulating anti-cancer therapeutics. ICP-189 is now in phase I clinical trial in China and United States.

In a phosphatase profiling assay, ICP-189 efficiently inhibits the catalytic activity of SHP2, with no significant effects on 21 other tested tyrosine and serine/threonine phosphatases, indicating its high selectivity for SHP2. ICP-189 has demonstrated robust in vitro efficacies in a panel of tumor cell lines bearing activated RTK, RAS, NF1 loss-of-function, or BRAF class III mutations. It has also exhibited synergistic tumor killing effects in combination with EGFR, KRASG12C, MEK and CDK4/6 inhibitors.

The in vivo efficacy of ICP-189 is well accompanied by pharmacodynamic modulations, where ICP-189 exposure levels correlate with reduced p-ERK and DUSP6 mRNA levels in tumors.

The pharmacokinetic parameters of ICP-189 are overall favorable, with high oral bioavailability.

Detailed abstracts can be found at AACR (Free AACR Whitepaper) official website.