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Immune-Onc Therapeutics Makes Two Presentations of IO-108, a Novel Clinical-Stage Myeloid Checkpoint Inhibitor Targeting LILRB2 (ILT4), at the American Association for Cancer Research (AACR) 2022 Annual Meeting

On April 8, 2022 Immune-Onc Therapeutics, Inc. ("Immune-Onc"), a private, clinical-stage cancer immunotherapy company developing novel biotherapeutics targeting myeloid checkpoints, reported two poster presentations on its clinical stage program IO-108, a novel myeloid checkpoint inhibitor targeting Leukocyte Immunoglobulin-Like Receptor B2 (LILRB2, also known as ILT4), at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Immune-Onc Therapeutics, APR 8, 2022, View Source [SID1234611751]).

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Tumor-associated myeloid cells are immunosuppressive cells that contribute to impaired anti-tumor responses, and limit the efficacy of currently approved cancer immunotherapies, such as T cell checkpoint inhibitors. LILRB2 is a receptor expressed primarily by myeloid cells that has several ligands known to contribute to immune suppression in the tumor microenvironment (TME).

"The pioneering work of our scientific team shows that IO-108 binds to LILRB2 with high affinity and specificity and blocks the interaction of LILRB2 with multiple immunosuppressive ligands. As a result, IO-108 activates and enhances anti-tumor immune responses ex vivo and inhibits the growth of solid tumors in preclinical models," said Charlene Liao, Ph.D., chief executive officer of Immune-Onc. "Collectively, these studies have enabled a comprehensive clinical biomarker plan and further support the ongoing Phase 1 clinical study of IO-108 as a novel immunotherapy for multiple solid tumor types, including those that are resistant to or relapsed after T cell checkpoint inhibitor treatments."

Ex vivo studies show that treatment with IO-108 produces pro-inflammatory activity and an enhanced antigen-presenting cell (APC) phenotype to multiple stimuli, including T cell activators, and STING and TLR agonists. As a single agent, IO-108 reverts the anti-inflammatory myeloid cell phenotype caused by "tumor conditioning" to pro-inflammatory phenotype and promotes the differentiation of monocytes and immature dendritic cells into pro-inflammatory dendritic cells, which are critical in generating productive anti-tumor immune responses.

IO-108 enhances the effect of PD-1 blocking antibodies in CD4+ T cell activation by allogeneic macrophages. Moreover, IO-108 monotherapy inhibits the growth of solid tumors in a preclinical model, which is associated with immune cell activation. Importantly, IO-108 presents a favorable pharmacokinetic and safety profile in preclinical models.

In the ongoing Phase 1 study of IO-108 in adult patients with advanced or refractory solid tumors (NCT05054348), IO-108 is studied at 60, 180, 600 and 1800 mg in monotherapy and at 180, 600 and 1800 mg in combination with 200 mg of pembrolizumab, administered intravenously every three weeks. IO-108 has been well-tolerated to date, both as a monotherapy and in combination with pembrolizumab, and dose-limiting toxicity has not been observed so far, at up to 600 mg in monotherapy and 180 mg in combination with pembrolizumab. Enrollment is ongoing with the last patient in expected in the second quarter of 2022.

Details of Immune-Onc’s AACR (Free AACR Whitepaper) 2022 presentations are as follows:

Abstract Number: 601
Title: IO-108, A fully human therapeutic antibody blocking the myeloid checkpoint LILRB2/ILT4, promotes innate and adaptive anti-cancer immunity in preclinical studies
Presentation Time: April 10, 2022, 1:30 PM – 5:00 PM ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 38

Abstract Number: CT209
Title: A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348)
Presentation Time: April 12, 2022, 9:00 AM – 12:30 PM ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 34

ABOUT LILRB2 (ILT4)

LILRB2, also known as ILT4, is expressed mostly by myeloid cells, including monocytes, macrophages, dendritic cells, and neutrophils. In solid tumors, activation of LILRB2 by its ligands, including HLA-G, ANGPTLs, SEMA4A, and CD1d, induces a tolerogenic phenotype in myeloid cells, thereby promoting poor T cell activation and consequent tumor immune evasion.

Orum Therapeutics Presents Preclinical Data at AACR 2022 Highlighting Novel Dual-Precision Targeted Protein Degrader, ORM-5029, Degrading GSPT1

On April 8, 2022 Orum Therapeutics, a private biotechnology company pioneering the development of tumor-directed targeted protein degraders (TPDs), reported that preclinical data for ORM-5029, a potential first-in-class TPD therapy for HER2-positive cancers, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022 (Press release, Orum Therapeutics, APR 8, 2022, View Source [SID1234611750]). ORM-5029 is one of two lead programs from the company’s Antibody neoDegrader Conjugate (AnDC) platform based on its Dual-Precision Targeted Protein Degradation (TPD²) approach.

ORM-5029 is designed to selectively deliver catalytic GSPT1 protein degraders to HER2-expressing tumor cells via antibody targeting. Orum developed a proprietary class of GSPT1 degrader molecules, paired them with a HER2-targeting antibody, pertuzumab, and screened numerous candidate conjugates to identify a molecule with the desired therapeutic profile. The data presented at AACR (Free AACR Whitepaper) 2022 describes initial preclinical evaluation of potency, efficacy, and pharmacodynamic (PD) response of ORM-5029.

"Targeted protein degradation holds much therapeutic promise, but classic TPD approaches face clinical development hurdles, including optimizing potency, exposure, and tolerability," said Peter U. Park, Ph.D., Chief Scientific Officer of Orum Therapeutics. "We believe that we can fulfill the promise of TPD by developing novel small molecule degraders combined with the precise cellular delivery mechanism of antibodies. Compared to either small molecule GSPT1 degraders or standard-of-care antibody drug conjugates, ORM-5029 exhibited superior in vitro and in vivo potency, robust efficacy in low-HER2 settings, and dose-dependent efficacy. These data provide compelling evidence to support our unique approach to targeted protein degradation and continue development of ORM-5029."

Key data takeaways:

ORM-5029 displays robust efficacy both in vitro and in vivo compared to other small molecule GSPT1 degraders and approved antibody drug conjugates (ADCs)
ORM-5029 exhibits potent activity in HER2-low models both in vitro and in vivo
Dose-dependent efficacy of ORM-5029 correlates with robust and rapid PD modulation of tumor GSPT1 protein levels
Orum’s proprietary payload, SMol006, is a potent degrader with high selectivity for GSPT1 and is compatible with any ADC linker and conjugation technologies.
AACR 2022 is taking place both virtually and in-person at the Ernest N. Morial Convention Center in New Orleans from April 8-13. The poster presentation titled, "ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer," will be available for viewing to registered attendees from Friday, April 8, through Wednesday, July 13, on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website. The poster (abstract # 3933) will be presented in person on April 13 from 9:00 am to 12:30 pm in Session PO.ET06.06 – Emerging New Anticancer Agents in Exhibit Halls D-H, Poster Section 22, Poster Number 7.

The poster is available on request; please email us at [email protected].

About Orum’s AnDC Platform

Orum’s Antibody neoDegrader Conjugate (AnDC) platform uses the Company’s unique Dual-Precision Targeted Protein Degradation (TPD²) approach to build novel targeted protein degraders (TPD) combined with the precise tumor cell delivery mechanisms of antibodies to generate innovative, first-in-class cell-specific TPD for the treatment of cancer. The company has developed new molecular glue degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, neoDegraders are designed to be delivered specifically to cancer cells and degrade the intracellular target protein and cause tumor cell death.

Orphagen Pharmaceuticals Presents Preclinical Efficacy Data at AACR 2022 on OR-449, a First-in-Class Steroidogenic Factor 1 Inhibitor, for the Treatment of Leydig Cell Tumors

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.

"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.

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]).

"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.

"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."