On April 7, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), reported that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024) (Press release, Ascentage Pharma, APR 7, 2024, View Source;ascentage-pharma-presents-results-from-three-studies-at-2024-american-association-of-cancer-research-annual-meeting-302109949.html [SID1234641849]). This year’s AACR (Free AACR Whitepaper) annual meeting will be held from April 5-10 2024, in San Diego, California, USA.

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"We are pleased to present the preclinical research data of four assets in our pipeline at the AACR (Free AACR Whitepaper) 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need."

The details of these three preclinical studies are as follows:

Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms

Abstract#: 1971

Time: Monday April 8, 2024, 9:00 AM – 12:30 PM (Pacific Time)

Introduction:

Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D).
Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors.
The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients.
Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action.
Conclusions:

Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo.
Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers.
Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines.
In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers.
Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa)

Abstract#: 3223

Time: Monday April 8, 2024, 1:30 PM – 5:00 PM (Pacific Time)

Introduction:

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies.
Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3.
MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis.
The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models
Conclusions:

In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis.
APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo.
Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis.
Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa.
APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC)

Abstract#: 4569

Time: Tuesday April 9, 2024, 9:00 AM – 12:30 PM (Pacific Time)

Introduction:

Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis.
FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes.
FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target.
The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer.
Conclusions:

APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines.
FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner.
APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model.
The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model.
These promising results support the future clinical development of this combination treatment for ovarian cancer.

On April 7, 2024 Laekna (2105.HK) reported that the company has presented two internally-discovered preclinical candidates, in addition to a poster presentation on a clinical trial, at the 2024 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in San Diego, California (Press release, Laekna Therapeutics, APR 7, 2024, View Source [SID1234641848]). The presentations featured preclinical data of two novel selective inhibitors, LAE119, a novel PARP1 selective inhibitor and trapper, and LAE120, a novel selective USP1 inhibitor.

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"After advancing LAE102, our internally discovered antibody against ActRIIA, into IND stage, Laekna continues to strengthen our internal discovery efforts, with new drug candidates emerging", said Dr. Justin Gu, Chief Scientific Officer of Laekna. "The MOA of LAE119 and LAE120 is synthetic lethality, both exhibit strong anti-tumor efficacy and good safety in preclinical models. LAE 119 is a PARP1-selective inhibitor with the strongest DNA-trapping activity among all the PARP inhibitors tested. It shows good activity even in tumor cells with low PARP1 protein level. LAE120 is a novel USP1 inhibitor currently at IND-enabling studies stage. It has a unique chemical scaffold differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. The quick advance of these two projects into PCC stage demonstrates the effectiveness of the close collaboration among Med Chem, Biology and AIDD (AI-driven Drug Discovery) teams. Laekna will continue our internal effort of discovery novel drug candidates to provide more options for patients."

Laekna’s internal discovery focuses on innovation, scarcity, and differentiation, covering three areas: cancer, metabolic diseases，and liver fibrosis. The company has internally discovered 14 drug candidates, among which seven have been optimized and advanced to PCC (pre-clinical candidate) stage. The company plans to have one drug candidate entering the clinical stage each year.

The Annual Meeting of AACR (Free AACR Whitepaper) is set for April 05 to 10, 2024 at the San Diego Convention Center, California, USA. It is the focal point of the cancer research community, where scientists, clinicians, other health care professionals, survivors, patients, and advocates gather to share the latest advances in cancer science and medicine. [1]

[1] View Source

Presentation details are as follows:

Title: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper

Authors: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu

Session Category: Experimental and Molecular Therapeutics

Session Title: DNA Damage and Repair

Session Date and Time: Wednesday, Apr 10, 2024 9:00 AM- 12:30 PM (PT)

Location: Poster Section 22

Poster Board Number: 27

Abstract Highlights:

LAE119 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than 1000-fold selectivity for PARP1 DNA trapping activity over PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays and shows good activity even in tumor cells with low PARP1 protein level. It demonstrates robust anti-tumor effect in BRCA2-/- DLD-1 and MDA-MB-436 Xenograft models and has minimal effects on hematologic parameters.

Full texts of the abstracts are available here.

Title: Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitors

Authors: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu

Session Category: Experimental and Molecular Therapeutics

Session Title: Novel Antitumor Agents 2

Session Date and Time: Sunday, Apr 7, 2024 1:30 PM- 5:00 PM (PT)

Location: Poster Section 27

Poster Board Number: 16

Abstract Highlights:

LAE120 is a novel, allosteric and highly potent USP1 inhibitor, displaying monotherapy potency and combination activity with PARP inhibitor in HRD (homologous recombination deficiency) cancers. It has a unique chemical structure differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. LAE120 shows robust tumor inhibitory activity in MDA-MB-436 and K562 xenograft models as a single agent and exhibits synergistic effect in combination with PARP inhibitors. LAE120 demonstrates good therapeutic window in DRF study and is currently at IND-enabling stage.

On April 7, 2024 Dizal (688192.SH) reported that the U.S. Food and Drug Administration ("FDA") has granted Breakthrough Therapy Designation (BTD) to its sunvozertinib as the first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations (Press release, Dizal Pharma, APR 7, 2024, View Source;patients-with-advanced-non-small-cell-lung-cancer-harboring-egfr-exon-20-insertion-mutations-302109862.html [SID1234641847]).

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This Breakthrough Therapy Designation (BTD) approval was based on results from the global multi-center phase I/II study (WU-KONG1). At 2023 ESMO (Free ESMO Whitepaper), Dizal reported main study results, showing sunvozertinib as a single agent with confirmed objective response rate (cORR) of 78.6% and a median progression-free survival (mPFS) of 12.4 months.

Sunvozertinib was previously granted BTDs by both the US FDA and the China Center for Drug Evaluation (CDE) for relapsed or refractory patients It was subsequently approved in China in 2023 for the treatment of patients who failed 1st line treatment. NDA submissions for US and EU approvals in the same setting is anticipated later in 2024.

"We are delighted with the FDA’s decision granting the Breakthrough Therapy Designation to sunvozertinib for first-line treatment, coming on the heels of earlier BTD approval in later lines of therapy — a clear indication of sunvozertinib’s transformative potential in the treatment of patients with EGFR exon20ins NSCLC. Multiple clinical trials have consistently demonstrated sunvozertinib’s significant clinical benefits to our patients. As a single, oral agent, it offers apparent advantages in both safety and patient compliance over chemotherapies and infusion." said Xiaolin Zhang, PhD, CEO of Dizal, "Now enrollment for the global pivotal study in relapsed and refractory setting (WU-KONG1 PART B) has been completed, and we are going to report the study results as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. A randomized global phase III study in the first line setting (WU-KONG28) is well underway. This new BTD will enable us work more closely with the FDA and accelerate its clinical development and regulatory submission."

Affecting roughly 2%-4% of NSCLC patients, EGFR Exon20ins mutations have been difficult to treat due to their unique spatial conformation, diverse mutation subtypes, and high heterogeneity. There has been a persistent lack of safe and effective targeted treatment options for this mutation, leading to limited survival benefits for patients.

Sunvozertinib’s innovative molecular structure enables it to overcome the inherent difficulties of targeting EGFR Exon20ins mutations, offering improved efficacy, safety, and ease of administration. Supported by findings yielded in the multicenter phase 2 pivotal study WU-KONG6, sunvozertinib was approved in China for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or following platinum-based chemotherapy, validating its potent and well-tolerated profile in previously treated NSCLC patients with EGFR Exon20ins mutations.

About Breakthrough Therapy Designation

The FDA’s Breakthrough Therapy Designation is intended to expedite the development and regulatory review of drugs for serious or life-threatening conditions. To qualify, new drugs must demonstrate promising preliminary clinical results indicating substantial improvement on clinically significant endpoints over existing treatments. Drugs designated as breakthrough therapies benefit from a suite of accelerated development policies, including close guidance by FDA experts throughout the clinical development process, significantly improving communication efficiency. Upon submission of a marketing application, such drugs may also be eligible for priority review if they meet relevant criteria.

About sunvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA for the treatment of advanced NSCLC with EGFR exon20ins mutations after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins mutations. The primary endpoint of the study, which was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins mutations.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug related TEAEs (treatment emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 PART B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR Exon20ins mutations.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).

On April 7, 2024 Geneos Therapeutics, a clinical stage biotherapeutics company focused on the development of personalized therapeutic cancer vaccines (PTCVs), reported the publication of positive safety, immunogenicity, and efficacy data from the full cohort of patients enrolled in its GT-30 clinical trial in Nature Medicine (Press release, Geneos Therapeutics, APR 7, 2024, View Source [SID1234641846]).

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The paper, titled, "Personalized Neoantigen Vaccine and Pembrolizumab in Advanced Hepatocellular Carcinoma: A phase 1/2 trial," details the GT-30 clinical trial, a 36-patient, single-arm, open-label, multi-center Phase 1/2 study of GNOS-PV02, a DNA plasmid encoded PTCV in combination with DNA plasmid encoded IL-12 (a cytokine adjuvant), and pembrolizumab (a PD-1 inhibitor) in second-line (2L) patients with advanced hepatocellular carcinoma (HCC) previously treated with a multi-tyrosine kinase inhibitor. The study met its primary endpoints of safety and immunogenicity and its secondary endpoint of efficacy based on observed response rate (ORR).

PTCV-related adverse events were all limited to Grades 1 and 2 with no dose-limiting toxicities or grade > 3 adverse events observed. The most common adverse events were injection site reactions observed in 41.6% (15/36) of patients. This is in contrast to typical immuno-oncology combination regimens, including those approved for first-line use in advanced HCC, wherein adding a second agent may lead to markedly increased toxicity; here, the addition of a PTCV to a PD-1 inhibitor was not observed to lead to any significant decrease in patient safety and tolerability.

The ORR for GT-30 is currently at 30.6% (11/36), including three complete responses (CR) and eight partial responses. This response is statistically significant based on pre-specified criteria at a one-sided p-value = 0.031 (1-sided 90% CI 20.4%-100%) versus a pre-specified historical control of 16.9% for pembrolizumab monotherapy. This historical comparator response rate was modeled on Phase 3 KN-240 data presented at ASCO (Free ASCO Whitepaper) 2019 and is also consistent with the prior Phase 2 KN-224 study. As an overall class, anti-PD1 monotherapy for 2L advanced HCC has shown response rates of 11%-18% in seven Phase 2 and Phase 3 clinical studies enrolling over 1400 patients. Additionally, the GT-30 CR rate of 8.3% (3/36) compares with a historical anti-PD-1 monotherapy CR rate in 2L of 0% – 3% in the prior studies. As of the data cutoff, the median OS (mOS) in GT-30 was 19.9 months compared to a mOS range of 12.9 – 15.1 months reported for the prior 2L studies of pembrolizumab and other anti-PD-1 monotherapy. 11 of 36 patients remain on treatment and, in total, 17 patients continue to be followed for overall survival (OS).

"Other recent industry trials have tested personalized cancer vaccines in patients with highly immune-sensitive tumor phenotypes and no measurable disease. In marked contrast, the GT-30 trial assesses PTCVs in HCC, a cancer with very low tumor mutational burden and an immune-excluded phenotype, and in patients with significant late-stage unresectable and metastatic disease," said Niranjan Sardesai, PhD, CEO and president of Geneos. "Despite the small size of this study, our results are important for the advancement of the field. We have not only met endpoints for safety, immunogenicity, and clinical efficacy based on ORR in this difficult to treat setting, but our mechanism of action data trace and confirm every step, from vaccination to tumor reduction, required to explain the immunological basis for the observed clinical responses."

Immunological analyses confirm the induction of new T cell responses to vaccine-encoded neoantigens in 14 of 14 (100%) evaluated patients and the expansion of this TCR repertoire both in the peripheral blood and tumors of PTCV-treated patients. Single cell sequencing analyses show the vast majority of these T cell clones to be CD8 T effector memory cells, a key requirement to induce anti-tumor cytotoxicity. In contrast, while anti-PD-1 monotherapy has been observed to reverse T cell dysfunction in existing neoantigen-specific T cell clones, it is not known to induce any new neoantigen-specific T cell clones.

Today Geneos also presented selected GT-30 clinical trial data and updated longitudinal circulating tumor DNA (ctDNA) biomarker data from the trial at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego. Reductions of at least 50% versus baseline in patient ctDNA, an exploratory endpoint, were seen in 40.7% of patients (11 of 27 patients for whom the full data set are available). All such responses correlate with ongoing survival.

"To our knowledge, the GT-30 clinical study provides the first definitive demonstration of a personalized cancer vaccine enhancing clinical response to anti-PD-1 therapy by inducing new, neoantigen-specific T cells which traffic to the tumor," said Ildiko Csiki, MD, PhD, chief medical officer of Geneos. "The fact that the PTCV regimen has produced this important result in a form of cancer as immunologically ‘cold’ as HCC, leading to multiple complete responses and a doubling of objective response versus PD-1, is incredibly promising and shows the therapeutic potential of personalized cancer vaccines for cancer patients."

DNA-based PTCVs may include up to 40 neoantigens. The majority of patients in the GT-30 study were administered PTCVs which included all of their targetable neoantigens across a broad range of predicted MHC binding affinity. A correlation was seen in GT-30 between the number of vaccine epitopes and the number of reactive epitopes post-vaccination, suggesting that having more neoantigens in the vaccine increased the effectiveness of tumor control. Other personalized vaccine platforms, especially those not based on DNA, have historically had to target a more limited selection of neoantigens, which may limit their efficacy.

On April 7, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, cardiovascular and metabolic, autoimmune, ophthalmology and other major diseases, reported that preclinical data on multiple novel bispecific antibodies as well as antibody-drug-conjugates (ADCs) from its oncology pipeline are presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (Press release, Innovent Biologics, APR 7, 2024, View Source [SID1234641845]).

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Late-Breaking Research: Experimental and Molecular Therapeutics 1

Topic: IBI3001: a potentially first-in-class site-specific glycan-conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors
Abstract Number: LB055
Presentation Form: Poster
Presentation Time: Sunday Apr 7, 2024 1:30 PM – 5:00 PM
Location: Poster Section 53
Presenting Author: Dr. Kaijie He

IBI3001 is a potentially first-in-class bispecific ADC against B7-H3 and EGFR that is site-specifically glycan-conjugated using the clinically validated SYNtecanE platform.

IBI3001 has multiple anti-tumor mechanisms of action: (1) enhanced EGFR signaling blockade; (2) EGFR- and B7-H3-aided payload internalization and cytotoxicity; and (3) potent bystander killing effects of ADC. The optimized B7-H3 arm not only enhances the EGFR signaling blockade but also reduces EGFR on-target toxicities.

IBI3001 showed strong anti-tumor efficacy in vitro and in vivo across multiple solid tumors and is well tolerated with the therapeutic index at 40.

Topic: IBI334, a novel ADCC-enhanced B7-H3/EGFR bispecific antibody, demonstrated potent pre-clinical efficacy in solid tumors
Abstract Number: LB056
Presentation Form: Poster
Presentation Time: Sunday Apr 7, 2024 1:30 PM – 5:00 PM
Location: Poster Section 53
Presenting Author: Dr. Kaijie He

IBI334 is an afucosylated bispecific antibody against B7-H3 and EGFR that is constructed using Innovent’s proprietary Innobody platform.

With the aid of B7-H3, IBI334 showed better tumor growth inhibition in vitro and in vivo than EGFR monoclonal antibody and c-met/EGFR bispecific antibody benchmarks.

IBI334 has a favorable safety profile with the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys at 120 mg/kg and a large therapeutic window of > 200 folds.

As a promising bispecific antibody against multiple solid tumors, IBI334 is currently under clinical evaluation.

Topic: Discovery and preclinical characterization of IBI343, a site-specific glycan-conjugated anti-Claudin18.2 ADC for treating solid tumors
Abstract Number: LB057
Presentation Form: Poster
Presentation Time: Sunday Apr 7, 2024 1:30 PM – 5:00 PM
Location: Poster Section 53
Presenting Author: Dr. Kaijie He

IBI343 is a potentially first-in-class anti-Claudin 18.2 ADC that is site-specifically glycan-conjugated to cytotoxin exatecan via Synaffix’s GlycoConnect technology.

It demonstrated Claudin 18.2-specific in vitro cytotoxicity on a series of cancer cell lines at varying levels of target expression, and potent in vivo efficacy in multiple xenograft models. The glycan-based conjugation technology leads to enhanced stability of the ADC molecule. IBI343 displayed good safety profile in GLP toxicology study in rhesus monkey and was well tolerated up to 30 mg/kg.

IBI343 has favorable pre-clinical efficacy and safety, and it is currently in preparation for Phase 3 clinical trial for Claudin-18.2-positive HER2-negative gastric cancer.

Dr. Kaijie He, Vice President of Innovent, stated: "We are pleased that the pre-clinical studies of our novel anti-cancer drugs are accepted for Late-Breaking Research poster presentation at the 2024 AACR (Free AACR Whitepaper) conference. This is the result of dedicated work from scientists at Innovent Academy with the aim to tackle cancers with innovative drugs that are more effective and safer. With careful design and optimization, our molecules can achieve favorable therapeutic windows of 40 to more than 200 times. We look forward to their performance in clinical settings and hope that these innovations can eventually benefit cancer patients."

Poster Session: Immunology – Single Target and Bispecific Antibodies

Topic: A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activity and acceptable safety
Abstract Number: 2718
Presentation Form: Poster
Presentation Time: Monday Apr 8, 2024 1:30 PM – 5:00 PM
Location: Poster Section 6
Poster Board Number: 9
Presenting Author: Dr. Huizhong Xiong

Immune stimulating antibody conjugates (ISACs) are a unique class of ADC in which antibodies recognizing tumor antigens are conjugated with immune agonists. ISACs target tumor tissue and specifically activate intra-tumoral myeloid cells, unleashing downstream immune response. Like the other immune agonists, balance between efficacy and safety remains a challenge for ISACs.

Here we describe a potential first-in-class TROP2 ISAC with rationally selected antibody and TLR7/8 agonist linker-payload. The anti-TROP2 antibody elicited robust ADCP of TROP2+ tumor cells by macrophages. In-vitro, TROP2 ISAC mildly activated myeloid cells only in the presence of TROP2+ tumor cells. In-vivo, the molecule potently suppressed tumor growth in different TROP2+ xenograft tumors, and effectively enhanced killing of an ADC. In terms of safety, the ISAC was tolerated in both WT and hTROP2KI mice, and, importantly, in monkeys.

Taken together, our data demonstrate a novel TROP2 ISAC with outstanding efficacy and manageable safety profile, which may benefit patients with TROP2+ tumors.

Poster Session: Immunology – Immune Modulation Employing Agonist or Co-Stimulatory Approaches

Topic: Tumor targeted-CD28 bispecific antibody with optimized potency, robust anti-tumoral activity and stringent CD3-dependence
Abstract Number: 5295
Presentation Form: Poster
Presentation Time: Tuesday Apr 9, 2024 1:30 PM – 5:00 PM
Location: Poster Section 3
Poster Board Number: 4
Presenting Author: Dr. Huizhong Xiong

We reported a rationally screened CD28 agonist antibody and its PSMAxCD28 bispecific format, IAR038.

IAR038 has minimal activity in the absence of CD3, even under stringent conditions, different from benchmark antibody in clinical development. It demonstrated moderate activity in vitro in a CD3-dependent and PSMA-dependent manner. Notably, IAR038 elicited superior tumor killing in vivo and combined effectively with anti-PD1 antibody.

In addition, it had an improved half-life compared with the Benchmark antibody. These features may translate to a wider therapeutic window and improved safety for CRPC patients.

Dr. Huizhong Xiong, Senior Director of Immunology of Innovent, stated: "We keep pushing for deeper understanding and more rational design of agonistic and costimulatory molecules. Our work on tumor targeted TLR7/8 agonist and tumor targeted CD28 antibody demonstrates the capability of our biology-driven drug development to achieve better balance between efficacy and safety, made possible by our advanced technology platforms."