Elpis Biopharmaceuticals Showcases Preclinical Data from its Transformative Multi-functional Immuno-Oncology Programs at 2022 AACR Annual Meeting

On April 8, 2022 Elpis Biopharmaceuticals, an IND stage biopharmaceutical company developing next generation immunotherapies to transform cancer treatment, reported two posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, occurring April 8-13, 2022 (Press release, Elpis Biopharmaceuticals, APR 8, 2022, View Source [SID1234611744]).

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"Our pipeline of innovative, multi-functional immunotherapeutics continues to expand and advance, with the goal of addressing the high unmet medical needs of relapse and resistant cancers to current immunotherapies," says Yan Chen, President and Chief Executive Officer at Elpis Biopharmaceuticals. "We are excited to showcase our latest breakthrough research."

Discovery of EPIM-001, a tumor targeted engineered IL2 with biased IL2Rβ agonist activities, Poster Number: LB214, Late-Breaking Research: Immunology 2, April 13th 9:00 AM-12:30PM

Key findings from this presentation include:

EPIM-001, an anti-PD-L1 tumor targeting IL2 agonist with reduced IL2Rα binding and enhanced IL2Rβ binding, activates CD8+ T Cells and NK cells better than WT IL2, whilst only weakly activating Tregs
EPIM-001 monotherapy significantly reduces tumor burden in a "cold" xenograft mouse model that is resistant to anti-PD-1/PD-L1 treatment
EPIM-001, Pembrolizumab combination is synergistic in TNBC model
IND filing for EPIM-001 planned for Q2 2022
Development of fully human anti-CD19 & CD22 bispecific tandem CAR-T for the treatment of resistant or relapsed B cell malignancies, Poster Number: LB002, Late-Breaking Research: Clinical Research 1, April 10 1:30 PM-5:00 PM

Key findings from this presentation include:

EPC-001 showed robust anti-tumor activities in vitro and demonstrated high target specificity with the ability of simultaneous target engagement in solution and on cells
Low dose of EPC-001 exhibited potent anti-tumor activity and persistence with favorable memory CAR-T phenotypes
EPC-001 is a promising candidate which may prevent target escape to overcome mono-specific CAR associated cancer resistance/relapse
EPC-001 is being studied in an investigator-initiated trial to treat CD19 CAR-T resistant/relapsed patients
"We are excited to present the preclinical studies of our two lead programs. EPIM-001, an IND-stage molecule, is a bispecific multi-functional tumor targeting IL2Rβ agonist engineered to selectively activate effector T cells and NK cells, potentially enhancing treatment of a broad range of solid tumors" said Kehao Zhao, Chief Scientific Officer of Elpis Biopharmaceuticals. EPC-001 is a fully human CD19/CD22 bispecific tandem CAR-T candidate currently being studied in an investigator-initiated trial. "We are encouraged by the mechanism of EPC-001 to engage and activate CAR-T cells through bispecific or mono-specific targeting, which indicates it may have the ability to prevent and overcome resistance induced by tumor antigen escape."

Presentations will be available on Elpis’ website at View Source

Asher Bio to Unveil Two New Immunotherapy Programs, a CD8+ T Cell Targeted IL-21 and a Cis-Targeted IL-2 for Cell Therapy Augmentation, at AACR Annual Meeting

On April 8, 2022 Asher Biotherapeutics (Asher Bio), a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported preclinical data for AB821, its CD8+ T cell cis-targeted interleukin-21 (IL-21) cytokine, which was designed to promote the function, survival, and reduced exhaustion of CD8+ T cells, and for its cis-targeted interleukin-2 (IL-2) fusion molecules, which were developed to specifically target engineered cells such as CAR-T cells, while exhibiting minimal effects on non-engineered or endogenous cells (Press release, Asher Biotherapeutics, APR 8, 2022, View Source [SID1234611743]). The data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, being held in New Orleans, Louisiana, April 8-13, 2022.

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"We are pleased to announce two new development programs today, reflecting the versatility and broad applicability of our cis-targeting technology, as well as its ability to rapidly produce highly selective molecules that target two different cytokines to two different cell types," said Ivana Djuretic, Ph.D., Chief Scientific Officer and Co-founder of Asher Bio. "Including AB248, we have now validated in nonclinical studies three distinct programs in under three years since our founding, each of which has demonstrated over 100 to 1000x selectivity for its intended immune cell target. Importantly, and consistent with our foundational hypothesis that cis-targeted immunotherapies might overcome the clinical limitations of existing immune-based medicines, this selectivity has translated into improved activity and tolerability across an array of preclinical models. We look forward to advancing each of these programs, while further leveraging the modularity of our platform, with the goal of building a differentiated portfolio of product candidates for the treatment of cancers, autoimmune and infectious diseases."

AB821: a CD8+ T Cell Targeted IL-21

Asher Bio designed AB821 to overcome the historical challenges of IL-21, including pleiotropic activation of multiple lymphoid and myeloid immune cell subsets, by focusing the IL-21 activity of AB821 to only CD8+ T cells – the immune cell type primarily responsible for anti-tumor efficacy – while avoiding activation of non-CD8 cells which may dampen overall anti-tumor efficacy and contribute to adverse effects. IL-21 can have beneficial effects on anti-tumor immune responses due to its ability to activate STAT3, a master transcription factor involved in a broad spectrum of adaptive and innate immune functions. Previously, wild-type IL-21 has demonstrated promising signs of efficacy in early clinical studies, but its utility has been hindered by toxicities and pleiotropic effects, such as suppression of antigen presentation in myeloid cells.

Asher Bio’s presentation at AACR (Free AACR Whitepaper) provides an overview of AB821, a cis-targeted and charge-modified IL-21. In a poster titled "Selective activation of CD8+ T cells by a CD8-targeted IL-21 results in enhanced anti-tumor efficacy and safety," Renee Greer, Ph.D., Senior Scientist, Immunology at Asher Bio, shared foundational nonclinical proof-of-concept data, demonstrating that AB821 exhibits greater than 1000-fold selectivity for CD8+ T cells over other cell types. In addition, a single dose of murine CD8-IL21 surrogate demonstrated activity in multiple syngeneic tumor models without inducing body weight loss. In the MC38 tumor model, for example, treatment with a single dose of CD8-IL21 as low as 0.1 mg/kg induced complete regression of established tumors without toxicity and, in cynomolgus monkeys, treatment with CD8-IL21 demonstrated improved exposure and tolerability over untargeted IL-21.

"We are excited to share the first preclinical data for AB821, our CD8+ T cell targeted IL-21 and the second product candidate in our pipeline," said Andy Yeung, Ph.D., Chief Technology Officer and Co-founder of Asher Bio. "Though early, these data buoy our confidence that AB821 fits our desired product profile as an IL-21 therapy that can selectively activate STAT3 signaling in CD8+ T cells to promote functionality, memory cell differentiation, and survival, all of which are complementary to the proliferation signal provided by IL-2 induced STAT5 activation. We believe AB821 could address unmet needs across tumor types that may have sub-optimal responsiveness to IL-2 and/or PD-1 therapies, and we look forward to advancing this program toward our planned IND filing in the second half of 2023."

In addition to exploring AB821 as a monotherapy, Asher Bio intends to evaluate AB821 with AB248, its engineered interleukin-2 (IL-2) immunotherapy. Asher Bio believes the combination of AB248 and AB821 could enhance efficacy by combining AB248’s proliferation signal with AB821’s non-overlapping and complementary mechanism of action, which optimizes functionality and prevents T cell exhaustion.

Cis-Targeted IL-2 for Cell Therapy Augmentation

Asher Bio designed its highly selective cis-targeted IL-2 fusion molecules to specifically target engineered cells such as CAR-T cells, while exhibiting minimal effects on non-engineered or endogenous cells, enabling superior activity and durability. Positive clinical outcomes of commercially available CAR-T cell therapies in the treatment of some hematological malignancies, as well as the promising results with T cell therapies observed in solid tumors, have stimulated further interest in these treatment approaches. Building on these findings, important efforts in T cell engineering are underway to improve key properties including engraftment, persistence, and expansion in the tumor microenvironment. Preclinical studies have demonstrated that the co-administration of an IL-2 therapy can enhance engineered T cell engraftment, persistence, and functionality. However, the clinical potential of utilizing IL-2 in combination with engineered T cell therapies is limited using current molecules due to the severe toxicity of high-dose IL-2 and the inadequate selectivity of existing engineered IL-2 variants, which expand multiple endogenous cell types in addition to transferred T cells.

Asher Bio will present new data at AACR (Free AACR Whitepaper) characterizing two IL-2 fusions, CAR-IL2 and EGFRt-IL2, and detailed their in vivo activity in tumor-bearing NSG mice infused with human CAR-Ts. CAR-IL2 and EGFRt-IL2 are distinct fusion molecules, both of which leverage cis-targeting to enable CAR-T cell restricted IL-2 signaling. CAR-IL2 targets the FMC63 CAR directly without blocking CD19 antigen recognition, enabling targeting of approved anti-CD19 CAR-T products. EGFRt-IL2 targets an EGFR tag co-expressed with the CAR.

In a poster titled, "CAR-targeted IL-2 drives selective CAR-T cell expansion and improves anti-tumor efficacy," Nathan Mathewson, Ph.D., Senior Scientist at Asher Bio, will demonstrate the specificity of CAR-IL2 and EGFRt-IL2. Both fusion molecules selectively induce phospo-STAT5 signaling resulting in greater than 100-fold preferential STAT5 activity in CAR-expressing cells, compared to CAR-negative cells. The ability of the fusion molecules to selectively expand CAR-Ts in vitro and in vivo was shown through a substantial and specific expansion of the infused CAR-Ts, with the CAR-T fraction increasing from approximately 50% of infused T cells to over 93% of T cells. Re-dosing with either CAR-IL2 or EGFRt-IL2 resulted in a significant re-expansion of CAR-T cells by over 500-fold after a long rest period in vivo. In addition, treatment with the CAR-IL2 molecule augmented the anti-tumor activity of CAR-T therapy in a preclinical model of leukemia, converting a suboptimal dose of CAR-T cells into a curative therapy by meaningfully expanding the low number of transferred CAR-T cells.

"Durable complete responses and survival in CAR-T-treated patients is correlated with CAR-T engraftment and expansion. The new data that will be presented at AACR (Free AACR Whitepaper) provide foundational proof-of-concept for our strategy of selectively boosting CAR-T cells post-adoptive transfer, in order to drive significantly better CAR-T expansion and, therefore, improved activity and durability," said Dr. Djuretic. "In addition, selective support of CAR-T cells and other engineered T cells may provide other benefits, such as decreasing the number of engineered T cells required at infusion, reducing the need for preconditioning, and allowing temporal control over cell activation. We are eager to advance our program forward, as we aim to deliver bespoke cis-targeted cytokines that can augment existing cell therapies without requiring the retrofitting of a novel receptor or other construct, and ultimately optimize therapeutic outcomes."

Asher Bio to Present New Preclinical Data Demonstrating Differentiated Profile of AB248, its Lead Cis-targeted IL-2 Immunotherapy, at AACR Annual Meeting

On April 8, 2022 Asher Biotherapeutics (Asher Bio), a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported new preclinical data further demonstrating the profile of AB248, an engineered interleukin-2 (IL-2) immunotherapy that it intends to develop for the treatment of cancer (Press release, Asher Biotherapeutics, APR 8, 2022, View Source [SID1234611742]). The data will be presented on Tuesday, April 12 in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, being held in New Orleans, Louisiana.

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"We are pleased to share new preclinical data across our portfolio at AACR (Free AACR Whitepaper), including for AB248, our lead product candidate," said Ivana Djuretic, Ph.D., Chief Scientific Officer and Co-founder of Asher Bio. "AB248 highlights our cis-targeting strategy, which optimizes the use of immunomodulators by selectively focusing their effect to specific immune cell types. By precisely activating only CD8+ T cells, the primary immune cell subset that drives anti-tumor efficacy in response to IL-2 pathway activation, we believe AB248 has the potential to deliver a highly differentiated product profile, that could become a backbone of immuno-oncology treatment across a range of solid tumors."

High dose IL-2 was the first modern immunotherapy to show complete responses in a subset of cancer patients, however this and second-generation ("not α") cytokine-based medicines are generally limited by off-target effects that both suppress anti-tumor responses and drive toxicity. In order to overcome these challenges, new approaches have emerged, which include targeting IL-2 to the tumor microenvironment or leveraging a cis-targeting approach to deliver IL-2 to specific immune cell subsets. AB248 is a cis-targeted immunotherapy, which was specifically engineered to selectively activate CD8+ T cells, which drive anti-tumor efficacy. AB248’s design allows for the avoidance of NK cells, which can act as a pharmacological sink and contribute to toxicity, as well as Tregs, which are immunosuppressive.

The new preclinical data to be presented at AACR (Free AACR Whitepaper) detail these selective properties of AB248, underscoring key areas of differentiation compared to other molecules in development. In a poster presentation, titled "AB248 is a CD8+ T Cell Selective IL-2 Designed for Superior Safety and Anti-Tumor Efficacy," lead author Kelly Moynihan, Ph.D., Director and AB248 Program Lead at Asher Bio, presents experiments showing that AB248 demonstrated selectivity, with an approximately 1000-fold preference for the activation of CD8+ T cells over NK cells and Tregs, and induced dose-dependent, selective expansion of CD8+ T cells in non-human primates.

Laboratory data also demonstrated that AB248 avoided the NK cell-dependent IFNγ secretion by cultured human peripheral blood mononuclear cells (PBMCs) that has been observed with first-generation IL-2 or second-generation "not α" IL-2s. In addition, data demonstrated that AB248 augments effector cytokine production in CD8+ T cells that also receive a T cell receptor signal. Unlike NK cells, CD8+ T cells do not produce inflammatory cytokines following an IL-2 signal alone.

"This new data demonstrates our ability to deconvolute complex biology by separating cell types essential for anti-tumor activity, like CD8+ T cells, from those that are key drivers of toxicity, and to leverage this understanding to develop potentially best-in-class molecules," said Dr. Djuretic. "Together with the results of preclinical studies we’ve shared previously, the new data presented at AACR (Free AACR Whitepaper) substantiate our belief in the clinical potential of AB248. We look forward to advancing AB248 into human testing later this year, where we plan to evaluate it in multiple solid tumor indications as both a single and combination agent."

Asher Bio continues to advance AB248 through preclinical studies. Asher Bio expects to file an IND application with the U.S. Food and Drug Administration in the third quarter of 2022 and plans to initiate a Phase 1 clinical trial before year-end.

The poster presentation is now available in the "Presentations and Posters" section of Asher Bio’s website: View Source

Palleon Presents Preclinical Data on Lead Program E-602 and Novel Bifunctional PD-L1-Targeted Sialidase

On April 8, 2022 Palleon Pharmaceuticals, a company pioneering the field of glyco-immunology to treat cancer and inflammatory diseases, reported that new preclinical data on the company’s lead oncology program, E-602, as well as data supporting Palleon’s novel bifunctional PD-L1-Targeted Sialidase, in two poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, La (Press release, Palleon Pharmaceuticals, APR 8, 2022, View Source [SID1234611741]).

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Data presented from non-human primate studies of E-602 (formerly Bi-sialidase) indicate that E-602 exhibits sustained, dose-dependent pharmacodynamic effects on desialylation of immune cells and a wide safety margin. E-602 produced dose-dependent effects on desialylation of immune cells, such as T cells, monocytes, and dendritic cells, with the effect of T cell desialylation sustained for up to seven days post-dosing. E-602 was well tolerated with NOAEL (Non-Observable-Adverse-Effect-Level) determined to be 100 mg/kg.

Additional data being shared at AACR (Free AACR Whitepaper) detail the development of Palleon’s novel bifunctional PD-L1-Targeted Sialidase, and initial in vitro and in vivo evaluation. The bifunctional PD-L1-Targeted Sialidase was constructed utilizing one chain of engineered human sialidase and a second chain of anti-PD-L1 antibody. In the human PD-L1-expressing mouse colon carcinoma model CT26, the PD-L1-Targeted Sialidase demonstrated modulation of immune cell infiltration in the tumor microenvironment and exhibited enhanced efficacy compared to a non-targeted sialidase or the anti-PD-L1 antibody.

"We’re pleased to share this first look at data from our bifunctional PD-L1-Targeted Sialidase. This molecule offers a novel immunotherapeutic approach of inhibiting two orthogonal checkpoint pathways by cleaving immunosuppressive sialic acids and blocking the PD-1/PD-L1 axis," said Li Peng, Chief Scientific Officer. "Additionally, we’re pleased with the encouraging pharmacodynamic effects and wide safety margin seen in IND-enabling GLP non-human primate toxicity studies for E-602, on the basis of which we have now advanced this program into Phase 1/2 study. We look forward to continuing to progress this study with the goal of making this novel immunotherapy available for patients with cancer."

The posters can be accessed via the "Publications" section of Palleon’s website.

Catamaran Bio Presents Preclinical In Vivo Efficacy Data Supporting Advancement of CAT‑179, a HER2-targeted Allogeneic CAR-NK Cell Therapy

On April 8, 2022 Catamaran Bio, Inc., a biotechnology company developing allogeneic, off‑the-shelf chimeric antigen receptor (CAR)-NK cell therapies to treat cancer, reported preclinical data showing that CAT-179, a cryopreserved, allogeneic HER2-targeted CAR-NK cell therapy, reduces tumor burden and extends survival in a HER2 mouse xenograft model. The results will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in New Orleans from April 8‑13, 2022 (Press release, Catamaran Bio, APR 8, 2022, View Source [SID1234611740]).

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"With these results, CAT-179 exemplifies the industry-leading capabilities of our TAILWIND platform to engineer off-the-shelf CAR-NK cell therapies with the features to overcome critical barriers to treat solid tumors," said Vipin Suri, PhD, MBA, Chief Scientific Officer of Catamaran Bio. "We are successfully integrating NK cell engineering with scalable and efficient cell processing and manufacturing to deliver on the promise of off-the-shelf CAR-NK cell therapies for solid tumors, and we are excited to be rapidly advancing CAT-179 toward the clinic."

Data presented in a poster titled, "Allogeneic Natural Killer Cells Engineered to Express HER2 CAR, Interleukin 15, and TGF beta Dominant Negative Receptor Effectively Control HER2+ Tumors," describe experiments showing key capabilities of the TAILWINDTM platform and characterization of the HER2-targeted CAR-NK cells. Highlights from the preclinical results include:

CAT-179 was efficiently engineered (45% CAR+) from donor-derived NK cells using the non-viral TcBuster transposon system, incorporating a multi-cistronic cargo containing HER2 CAR, IL15, and TGFβ dominant negative receptor (TGFβ DNR). The result was stable expression of the construct without the need for post-engineering selection.
CAT-179 demonstrated HER2-CAR-driven interferon gamma production and tumor cell killing in vitro when co-cultured with HER2+ tumor cells.
The TGFβ DNR in CAT-179 demonstrated resistance to TGFb-mediated immunosuppression in vitro.
CAT-179 cells persisted in vitro without the need for exogenous cytokines and showed significantly enhanced in vivo persistence up to at least 40 days in mouse models.
CAT-179 showed potent anti-tumor activity against a xenografted HER2+ ovarian cancer cell line (SKOV3), leading to a substantial survival benefit in tumor-bearing mice. Overall, CAT-179 treated animals demonstrated tumor reduction of 98% compared to control animals (p<0.019 two-tailed t-test) and had a median survival of 114 days vs. control animal median survival of 60 days.
The poster is available on the publications and presentations section of the Catamaran Bio website.