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NeoTX Therapeutics to Present at the Society for Immunotherapy of Cancer’s 36th Annual Meeting

On November 9, 2021 NeoTX Therapeutics, Ltd. (NeoTX), a clinical-stage immuno-oncology company, reported a presentation on the company’s lead program, naptumomab estafenatox (NAP), at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting being held November 10-14, 2021 at the Walter E. Washington convention Center, Washington D.C (Press release, NeoTX, NOV 9, 2021, View Source [SID1234594928]). The poster presentation will highlight preclinical data demonstrating that NAP enhances CAR-T cells potency and can boost CAR-T efficacy against solid tumors.

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Details on the poster presentation are as follows:

Title: Tumor Targeted Superantigen (TTS), Naptumomab Estafenatox (NAP), enhances CAR-T cells potency and can boost CAR-T efficacy against solid tumors
Abstract Number: 576 (ePoster)
Lead Author: Yael Sagi, Ph.D.
Category: Combination Immunotherapies
Date & Time: The ePoster will be on display on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform from 7 a.m. EST on Friday, Nov. 12, 2021 until the virtual meeting platform is closed on Jan. 9, 2022.

HUYABIO Announces the Exclusive License of the Wee1 Inhibitor from Shanghai Pharmaceuticals

On November 9, 2021 HUYABIO International, the leader in accelerating global development of China’s pharmaceutical innovations, reported it had licensed exclusive worldwide ex-China rights to the Wee1 inhibitor from Shanghai Pharma, the second largest pharma group in China with annual sales of over $30 billion (Press release, HUYA Bioscience, NOV 9, 2021, View Source [SID1234594927]). This is the first program that Shanghai Pharma has outlicensed to a global partner.

"HUYABIO International has pioneered an innovative approach for partnering with Chinese research institutions and pharmaceutical companies. It identifies and licenses the most promising pre-clinical and clinical stage compounds in China, leverages and extends the research efforts of its Chinese partners, and provides a bridge into the international development process and global biopharma market. We are glad to collaborate with them on our SPH6162 as this collaboration is an important milestone of our global strategy due to our Licensed Molecules and Licensed Products," said Min Zuo, CEO Shanghai Pharmaceuticals.

Wee1 regulates the G2 checkpoint and stimulates entry into mitosis in response to DNA damage. It is a nuclear kinase belonging to the Ser/Thr family of protein kinases and its cell size by inhibiting Cdk1. Wee1 over-expression has been observed in solid tumors including hepatocellular carcinoma, colon cancer, glioblastoma, non-small-cell lung cancer (NSCLS), neuroblastoma, and gastric cancers.

Dr. Mireille Gillings, CEO & Executive Chair of HUYABIO, said, "We are delighted to partner with Shanghai Pharmaceuticals for a therapeutic mechanism that promises broad synergy across treatments for many tumor types. HUYABIO is the first global company with which Shanghai Pharma has signed a major outlicensing agreement and we look forward to co-development of this innovative program in China."

HotSpot Therapeutics to Present New Data Indicating Successful Targeting of CBL-B at 2021 Society for Immunotherapy of Cancer Annual Meeting

On November 9, 2021 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first-in-class allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported new data validating its Smart Allostery platform in the elucidation and preclinical evaluation of a novel allosteric inhibitor of the E3 ubiquitin ligase CBL-B (Press release, HotSpot Therapeutics, NOV 9, 2021, View Source [SID1234594926]). The data will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting, which is being held from November 10-14, 2021.

"CBL-B’s role as a master negative regulator of T cells and NK cells makes it a very attractive target for cancer immunotherapy, but it has proven difficult to inhibit with traditional small molecules," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer at HotSpot Therapeutics. "We’re thrilled to share these new data showing that we can successfully inhibit CBL-B with a novel allosteric inhibitor identified through our Smart Allostery platform and promote T cell responses in vitro and in mice. To better treat patients, we need new mechanisms to enhance and sustain effective anti-tumor immunity and to address suboptimal responses. Our small molecule allosteric inhibitor of CBL-B may bring such benefit with the added advantage of convenient oral delivery."

CBL-B sits at a pivotal node in immune cell activation, and its inhibition holds the potential to address several key mechanisms where translational data supports a causative role in suboptimal response to current immunotherapies. Because inhibition of CBL-B lowers the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, it may bring benefit to patients with low antigen levels (e.g., low TMB), low inflammation (e.g., low PDL-1) and/or sub-par co-stimulation (e.g., low CD28).

HotSpot’s Smart Allostery approach offers a diversity of advantages in delivering highly selective and differentiated orally bioavailable medicines against proteins that are undruggable or poorly druggable targets, including CBL-B. The platform utilizes a suite of computational algorithms powered by machine learning to uncover natural hotspots that control protein function, employs an array of specialized assays to identify hotspot binders and subsequently uses chemistry to selectively drug these sites with allosteric inhibitors.

SITC Presentation Overview:

Title: Identification of A Novel Allosteric Oral CBL-B Inhibitor that Augmented T Cell Response and Enhanced NK Cell Killing in vitro and in vivo
Authors: Jun Kuai, Yingzhi Bi, Yilin Qi, Deborah G Conrady, Rajiv G Govindaraj, Graham Hone, R. Aldrin Denny, Ken Carson, Geraldine Harriman, Fang Wang
Poster Number: 864
Session: Novel Single-Agent Immunotherapies

Summary of Poster

CBL-B is activated by tyrosine kinases and undergoes a large conformational change from closed inactive form to open active form.
Through the utilization of HotSpot’s proprietary Smart Allostery platform, including its AI-powered SpotFinder technology, a druggable phosphoregulatory pocket was identified in the inactive form of CBL-B.
HotSpot identified an inhibitor that binds to a regulatory hotspot on CBL-B, locking it in its inactive form, as confirmed by co-crystal structures.
This molecule prevents CBL-B phosphorylation, inhibits E3 ligase activity, promotes cytokine release, enhances T cell proliferation, and stimulates NK cell activation/killing.
In vivo, the molecule enhances T cells responses in anti-CD3 treated mice.

Vigeo Therapeutics Announces New Phase 1/2 Data from its Expansion Study of VT1021 at the Society for Immunotherapy of Cancer’s 2021 Annual Meeting

On November 9, 2021 Vigeo Therapeutics, a clinical-stage immuno-oncology company pioneering novel cancer therapies, reported new clinical data from its Phase 1/2 expansion study evaluating the single-agent activity of VT1021 in subjects with pancreatic cancer and recurrent glioblastoma (rGBM) (Press release, Vigeo Therapeutics, NOV 9, 2021, View Source [SID1234594925]). The data is being presented in the poster session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 2021 Annual Meeting, taking place from November 10-14, 2021.

VT1021 is a first-in-class compound that induces the expression of Tsp-1 in the tumor microenvironment (TME). Tsp-1 then blocks the CD47 immune checkpoint and reprograms the CD36 receptor to induce tumor cell apoptosis, inhibit angiogenesis, and reprogram macrophages from the M2 to M1 phenotype. In the completed open-label, multicenter Phase 1/2 study (NCT03364400), the safety and preliminary anti-tumor efficacy of single-agent VT1021 was evaluated in subjects enrolled in both dose escalation and dose expansion cohorts. Results of the all-comer escalation cohort were presented at SITC (Free SITC Whitepaper) in 2020. In 2021, Vigeo is presenting the results of the expansion cohorts, which focused primarily on pancreatic cancer and rGBM, as well as other indications.

In the pancreatic cancer expansion cohort, VT1021, when administered as a single agent, was able to induce a reduction in tumor volume in 38% of subjects with measurable disease. VT1021 was able to reprogram the immune reactivity of the TME as evidenced by an increase in cytotoxic T lymphocytes (CTLs) as well as in the ratio of M1:M2 macrophages. These findings suggest that VT1021, in addition to its single agent activity, could be a potent and synergistic combination with checkpoint inhibitors.

Consistent with the reprogramming of the TME, Tsp-1 expression was significantly increased by VT1021 treatment across all tumor types. Induction of Tsp-1 protein was observed in circulating PBMCs, platelets and plasma, along with mRNA levels in PBMCs. Additionally, analysis of paired biopsy samples revealed increased Tsp-1 accumulation in MDSCs in the TME. Taken together these findings validate of the biological activity of VT021 via the induction of Tsp-1 in the TME.

"We are highly encouraged by the new data being presented at SITC (Free SITC Whitepaper), which demonstrate both a favorable safety profile for VT1021 as well as early signals of efficacy in pancreatic cancer – especially for those subjects with tumors expressing high levels of both CD47 and CD36," said CEO Jim Mahoney, "Out of 14 patients, 5 patients showed reduction in tumor burden. Based on these findings, we believe that VT1021, a dual-CD47/CD36 modulating agent, has strong potential as a treatment for pancreatic cancer patients."

Vigeo plans to initiate Phase 2/3 studies in both pancreatic cancer and rGBM during the first half of 2022. Vigeo will present additional results from the GBM expansion cohort at the Society for Neuro-Oncology (SNO) Conference in November 2021 in Boston, MA.

Details for the SITC (Free SITC Whitepaper) 2021 presentations are as follows:

Title: Clinical update of VT1021, a first-in-class CD36 and CD47 targeting immunomodulating agent, in subjects with pancreatic cancer and other solid tumors stratified by novel biomarkers
Presenter: Marsha Crochiere, PhD, Director of Translational Sciences, Vigeo Therapeutics
Session: Virtual Poster Hall
Poster #: 369
Date and time: A copy of the poster will be available on-demand starting Friday, November 12th at 7:00 AM ET

Title: Development of Thrombospondin-1 as a clinical pharmacodynamic biomarker for VT1021, a first-in-class therapeutic agent that reprograms the tumor microenvironment.
Presenter: Jian Jenny Chen, PhD, Director Scientific Research and Development, Vigeo Therapeutics
Session: Virtual Poster Hall
Poster #: 375
Date and time: A copy of the poster will be available on-demand starting Friday, November 12th at 7:00 AM ET

About VT1021
Vigeo’s lead asset, VT1021, is a first-in-class dual modulating compound that blocks the CD47 immune checkpoint and activates the apoptotic and macrophage reprogramming activity of CD36. The result of the dual modulating activity is the induction of apoptosis as well as an increase in both CTL:Treg and M1:M2 macrophage ratio. The biological/therapeutic activity of VT1021 is mediated by the stimulation of thrombospondin-1 (Tsp-1). Through these dual-modulating effects VT1021 reprograms the tumor microenvironment (TME) from one that is immune suppressive, or "cold," to immune enhanced (or sensitized), or "hot," that are more susceptible to attack from the immune system. Vigeo is developing VT1021 as a therapeutic agent across a range of cancers, with a current focus on solid tumors.

I-Mab and ABL Bio Report Preclinical Data of 4-1BB-targeting Bispecific Antibodies at 2021 SITC

On November 9, 2021 I-Mab (Nasdaq: IMAB), a clinical-stage biopharmaceutical company committed to the discovery, development, and commercialization of novel biologics, and ABL Bio, Inc. (Kosdaq:298380, hereafter "ABL"), a clinical-stage biotech developing bispecific antibody technology for immune-oncology and neurodegenerative diseases, reported preclinical data of their 4-1BB bispecific antibodies at the 2021 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, I-Mab Biopharma, NOV 9, 2021, View Source [SID1234594924]). The new data demonstrate the unique mechanisms of action of TJ-CD4B/ABL111 and TJ-L14B/ABL503 which have resulted in localized drug action and reduced systemic toxicity, as well as sustained anti-tumor efficacy.

Stimulation of 4-1BB is a promising therapeutic strategy for improving the current immunotherapy for multiple cancers. TJ-CD4B/ABL111 and TJ-L14B/ABL503, both jointly developed by I-Mab and ABL, are undergoing phase 1 clinical studies in the United States.

"Bispecific antibodies are rapidly recognized for their transformative potential, and our pipeline of highly-differentiated 4-1BB bispecific therapies are key components of our biologics pipeline development strategy," said Dr. Taylor Guo, Chief Scientific Officer of I-Mab. "Dose-limiting toxicities have hampered clinical development of 4-1BB targeting molecules as a drug class. The studies being presented at SITC (Free SITC Whitepaper) suggested that both our bispecific assets could have the ability to overcome this common problem, and we are confident that this differentiation places TJ-CD4B/ABL111 and TJ-L14B/ABL503 at the forefront of 4-1BB bispecific development."

"The preclinical data from this pair of bispecific molecules prove that our ‘Grabody-T’ platform effectively reduces peripheral toxicity by allowing the activation of T cells only in the tumor microenvironment," said Dr. Sang Hoon Lee, CEO of ABL Bio. "We look forward to further validating its therapeutic potential in the ongoing clinical studies and as we continue to develop 4-1BB bispecific antibodies in various cancer indications."

Key data highlights:

TJ-CD4B/ABL111

Poster title (#702): TJ-CD4B (ABL111), a Claudin18.2-targeted 4-1BB tumor engager induces potent tumor-dependent immune response without dose-limiting toxicity in preclinical studies

The preclinical studies confirmed the unique pharmacodynamic data and safety of TJ-CD4B/ABL111 in animal models and cell cultures. Analysis of the data found:

Potent, anti-tumor activity was observed with the proliferation of immune cells in the tumor microenvironment (TME) as well as an increase in memory T cells in the peripheral blood, suggesting long-term immunity against the tumor.
TJ-CD4B/ABL111 was well tolerated in non-human primates and did not induce a systemic immune response or liver toxicity up to levels of 100mg/kg.
Activation of immune pathways by TJ-CD4B/ABL111 was demonstrated by a pro-inflammatory profile and increased gamma interferon-regulated gene expression in primary human CD8+ T cells co-cultured with CLDN18.2 expressing cells.
TJ-L14B/ABL503

Poster title (#892): ABL503 (TJ-L14B), PD-L1x4-1BB bispecific antibody induces superior anti-tumor activity by PD-L1-dependent 4-1BB activation with the increase of 4-1BB+CD8+ T cells in tumor microenvironment

The preclinical study data confirms the unique mechanism of action of TJ-L14B/ABL503 and its potential to treat resistance to PD-L1 therapies. Analysis of the data found:

PD-L1-dependent stimulation of the 4-1BB signaling pathway was demonstrated in 4-1BB bioassays with PD-L1 expressing tumor cells
More potent 4-1BB activation by TJ-L14B/ABL503 was observed at higher PD-L1 expression confirming the requirement of PD-L1 on both tumor and immune cells for optimal activity. Cytokine release assays have also demonstrated minimal peripheral toxicity with TJ-L14B/ABL503
The in vivo efficacy of TJ-L14B/ABL503 was demonstrated in animal models with tumors expressing different levels of PD-L1. TJ-L14B/ABL503 showed anti-tumor efficacy across the PD-L1 levels. In particular, TJ-L14B/ABL503 demonstrated superior anti-tumor efficacy than atezolizumab in tumors with low PD-L1 expression
In vitro tumor-killing activity of TJ-L14B/ABL503 was superior compared to atezolizumab when tested in organoid system, even in organoids from atezolizumab non-responders
Pharmacodynamic changes in TILs and blood were evaluated in animal models. An increase in 4-1BB+ cells, CD8+ T cells, and effector memory T cells was observed in the TME and blood, indicating a strong and long-lasting anti-tumor immune response
Treatment with TJ-L14B/ABL503 increased MIG/CXCL9, MIP-1b/CCL4, and s4-1BB in the serum, and can potentially be used as pharmacodynamic markers in clinical trials
About TJ-CD4B/ABL111

TJ-CD4B, also known as ABL111, is a Claudin 18.2 and 4-1BB bispecific antibody capable of binding to tumor cells expressing Claudin 18.2, i.e., gastric cancer and pancreatic cancer cells, and stimulating intra-tumoral T cells by the 4-1BB arm designed to be activated only upon tumor engagement while silent elsewhere. TJ-CD4B/ABL111 effectively maintains a strong tumor binding property and anti-tumor activity attributable to a synergistic effect of both Claudin 18.2 antibody and 4-1BB antibody while it avoids or minimizes liver toxicity and systemic immunotoxicity commonly seen with 4-1BB antibodies as a drug class. Being developed under collaboration between I-Mab and ABL, TJ-CD4B/ABL111 is currently being investigated in a phase 1 clinical study in the U.S.

About TJ-L14B/ABL503

Being developed jointly with ABL, TJ-L14B/ABL503 is a differentiated PD-L1-based bispecific antibody with the PD-L1 arm as the tumor-dependent T-cell activator and the 4-1BB arm as the conditional T cell activator upon tumor engagement. Using ABL’s "Grabody-T" bispecific antibody platform technology, TJ-L14B/ABL503 stimulates 4-1BB activation only in the presence of PD-L1 expressing tumor cells to minimize the risk of off-tumor toxicity. Preclinical studies have demonstrated that the bispecific antibody shows better anti-tumor activity than equimolar doses of single agents alone or in combination. Phase 1 study in currently being conducted in the U.S.