On April 8, 2022 Orphagen Pharmaceuticals Inc., a biotech company pioneering the screening, discovery, and development of small molecule ligands that modulate orphan or unexplored members of the nuclear receptor family, reported a late-breaking presentation of new preclinical data for OR-449 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 being held April 8-13 both virtually and in-person in New Orleans (Press release, Orphagen, APR 8, 2022, View Source [SID1234611749]). The data presented demonstrate efficacy in a preclinical model of a Leydig cell tumor (LCT) of OR-449, the company’s first-in-class small molecule antagonist to the nuclear receptor steroidogenic factor-1 (SF-1 or NR5A1) and support the continued development of OR-449 as a novel targeted therapy for the treatment of LCTs as well as adrenocortical cancer (ACC), the primary indication for which it is being developed.

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"OR-449 was strategically designed at Orphagen and is the first antagonist to SF-1 to be taken into development – potent and orally bioavailable small molecules of this class have not previously been identified," said Scott Thacher, Ph.D., CEO and Founder of Orphagen. "The data presented at AACR (Free AACR Whitepaper) 2022 demonstrate that OR-449, a potent SF-1 antagonist, has clear potential for clinical efficacy in malignant LCTs as well as ACC. There is an urgent need for new therapies for LCT and ACC, and we are focused on completing IND-enabling studies of OR-449 with the goal of filing an investigational new drug application by the end of the year."

The incidence of ACC in the U.S. is 300 patients per year, and existing therapies are very limited. LCTs represent about 3% of all testicular cancers. Testicular cancer is in turn one of the most frequently diagnosed cancers in American males between the ages of 15 and 35. Malignant LCTs, though rare, are an estimated 10% of all LCTs. They are resistant to chemotherapy and radiation, responding primarily to surgery. Median survival from diagnosis is two years for these patients.

Summary of Results

OR-449 exhibits striking anti-proliferative activity in the rat Leydig tumor cell (LCT) line R2C, inhibiting DNA synthesis by >90% at 1 mM with an estimated IC50 of 68 nM.
In cell lines lacking SF-1 expression, such as HEK293, OR-449 has no anti-proliferative activity up to 20 mM, indicating that the anti-proliferative effect on R2C is SF-1-mediated and is not due to cytotoxicity.
OR-449 inhibits R2C xenograft tumor growth in immunocompromised mice at oral doses of 3, 10, and 30 mg/kg/day, with complete inhibition at a daily dose of 30 mg/kg.
Based on an mRNA response signature first identified in R2C culture, OR-449 appears to directly engage with SF-1 in the R2C tumors.
The in vivo potency and efficacy of OR-449 in the R2C model corresponds to what we previously reported for SJ-ACC3 (Crowe et al, ENDO 2021), a pediatric ACC patient-derived tumor xenograft (PDX) model.
These results highlight that OR-449 antagonism of SF-1 is a novel targeted therapeutic approach with potential utility in the treatment of ACC and malignant LCTs. Orphagen has initiated IND-enabling studies of OR-449 with an anticipated IND-filing date at the end of 2022.

The poster (abstract #LB144) titled, "Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors," will be available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website for registered attendees to view from Friday, April 8 through Wednesday, July 13. The poster will also be available via the company on request. The poster will be presented in person on Tuesday, April 12 from 9 am to 12:30 pm CT at the New Orleans Convention Center, Exhibit Halls D-H, Poster Section 27, Poster Board Number 17.

The authors acknowledge the support of the following NIH grants: R43 DK 102221, R43 CA 150540, R43 HD 068078, R43 CA 099875, R44 CA 265639.

Reference: Crowe, et al. A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010

About OR-449

OR-449 is the lead candidate identified from Orphagen’s proprietary screening technology, which has led to successful discovery of the first drug-like small molecules to several orphan nuclear receptors. OR-449 is a first-in-class, orally bioavailable small molecule antagonist to SF-1, an orphan nuclear receptor that is essential for the embryonic growth and development of adrenal and gonadal tissues. Clinical targets for SF-1 antagonism by OR-449, such as ACC and malignant LCT, are derived from these tissues and express very high levels of this novel drug target.

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

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."

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

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.