New Phase 1 Dose Escalation Data Show Well-Tolerated Safety Profile and Anti-Tumor Activity for Aulos Bioscience’s AU-007 at Society for Immunotherapy of Cancer (SITC) Annual Meeting

On November 3, 2023 Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through the development of best-in-class IL-2 therapeutics, reported new data from its Phase 1/2 clinical trial of AU-007 at the 38th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in San Diego, California (Press release, Aulos Bioscience, NOV 3, 2023, View Source [SID1234636878]). The data, from Phase 1 dose escalation cohorts, continue to indicate that AU-007 is well tolerated as a monotherapy treatment or in a combination therapy regimen with low-dose, subcutaneous aldesleukin (recombinant human IL-2). The data also demonstrate early evidence of anti-tumor activity in patients with several solid tumor cancer types.

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"These encouraging new data support AU-007’s distinct advantages in the IL-2 class," said Aron Knickerbocker, Aulos Bioscience’s chief executive officer. "AU-007 continues to be well tolerated by patients, with no pulmonary or generalized edema, no vasculature leakage, and no dose-limiting toxicity to date. We are particularly encouraged by the initial signs of clinical efficacy that have been seen even during dose escalation, which show that heavily pre-treated patients are benefiting from a treatment regimen of AU-007 dosed in combination with low doses of aldesleukin. At this point, we are observing the greatest anti-tumor activity in patients with tumors known to be sensitive to immune-modulating drugs. Tumor shrinkage has been observed in patients with melanoma, bladder, kidney and lung cancers. These data support our decision to focus our Phase 2 expansion cohorts in melanoma, renal cell carcinoma and non-small cell lung cancer. We look forward to presenting clinical data from the Phase 2 expansion cohorts next year."

Created by Biolojic Design, AU-007 is the first human IgG1 monoclonal antibody designed using artificial intelligence to be tested in a clinical trial. Unique among interleukin-2 (IL-2) therapeutics in development, the antibody’s computational design allows it to bind precisely to the portion of IL-2 that binds to CD25. Consequently, AU-007 prevents IL-2 from binding to high-affinity IL-2 receptors on regulatory T cells (Tregs), vasculature, pulmonary tissue and eosinophils, and redirects IL-2 to medium-affinity receptors on effector T cells (Teffs) and natural killer (NK) cells. This novel mechanism of action allows Teffs and NK cells to expand and kill tumor cells.

The Phase 1 data presented at SITC (Free SITC Whitepaper) is based on 42 patients who received study treatment as of October 13, 2023. AU-007 alone or in combination with aldesleukin was generally well tolerated as administered in the following cohorts:

Arm 1A as a monotherapy treatment up to 12 mg/kg
Arm 1B with 4.5 mg/kg of AU-007 and escalating aldesleukin (up to 270K IU/kg) given only once on Day 1
Arm 1C with 4.5 mg/kg of AU-007 in combination with aldesleukin (up to 135K IU/kg) also given every two weeks
All drug-related adverse events were Grade 1 or 2, with the exception of three transient Grade 3 or 4 lymphopenias that were not associated with adverse outcomes in patients receiving AU-007 and aldesleukin. Transient lymphopenia is a known effect of IL-2 treatment. No patients were discontinued for a drug-related adverse event and no dose-limiting toxicities were observed.

Additionally, preliminary evidence of anti-tumor activity was observed in heavily pre-treated patients, including in patients with melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) whose tumors had progressed through checkpoint inhibitors. Of note, CT scans of a patient with melanoma, who had progressed on anti-CTLA-4 and anti-PD-1 therapy without a response, show a 40% decrease in target tumor lesions, with shrinkage beginning at eight weeks and shrinking further at weeks 16 and 24. The patient continues on the study. Scans of a second patient with RCC, whose tumors had progressed through prior anti-PD-1 therapy, show 20% shrinkage in target tumor lesions beginning at eight weeks, and the patient continues on the study. Across the Phase 1 dose escalation cohorts, nine of 33 (27%) tumor evaluable patients had a best response of stable disease, and 16 patients continue treatment as of the data cutoff date.

As previously reported in October, new pharmacodynamic data from the Phase 1 dose escalation study show favorable trends toward decreasing Tregs with concordant increases in the CD8 Teff:Treg ratio, initial interferon-gamma increases, and absolute eosinophil decreases. These findings are consistent with the novel mechanism of action of AU-007 redirecting IL-2 away from the cells that express high-affinity IL-2 receptors that contain CD25, which include Tregs, vascular endothelial cells and eosinophils, and toward CD8 Teff cells and NK cells that can elicit anti-tumor immune effects.

The Phase 1/2 clinical trial of AU-007 is a two-part, open label, first-in-human study evaluating the safety, tolerability, immunogenicity and clinical activity of AU-007 in patients with unresectable locally advanced or metastatic cancer. The trial is currently enrolling patients at multiple locations in the United States and Australia. The company anticipates transitioning to the Phase 2 portion of the AU-007 study by late 2023 or early 2024, with Phase 2 dose expansion cohorts planned in melanoma, RCC and NSCLC.

The poster presentation is available on the Aulos Bioscience website in the Abstracts and Publications section.

To learn more about the AU-007 clinical trial program, please visit ClinicalTrials.gov (identifier: NCT05267626). For patients and providers in the U.S., please visit www.solidtumorstudy.com. For patients and health professionals in Australia, please visit www.solidtumourstudy.com.

About AU-007
AU-007 is a computationally designed, human IgG1 monoclonal antibody that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 leverages IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to CD25-containing receptors on eosinophils, as well as vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy.

Allogene Therapeutics Presents Preclinical Data on Next Generation Cloak™ and Dagger™ Technologies at the Society for Immunotherapy of Cancer Annual Meeting

On November 3, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported data highlighting the Company’s next generation Cloak and Dagger technologies designed to help enhance engraftment, expansion and the persistence of AlloCAR T cell candidates, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023, in San Diego, CA (Press release, Allogene, NOV 3, 2023, View Source [SID1234636877]).

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The development of "off-the-shelf" CAR T products that utilize cells from healthy donors has the potential to make CAR T therapies scalable and accessible to more patients. However, the effectiveness of allogeneic CAR T cells requires controlling rejection of the allogeneic CAR T cells by the patient’s immune system. Allogene’s proprietary Cloak and Dagger technologies are two novel strategies the Company is investigating to help control immune rejection and enhance expansion, persistence, and performance of AlloCAR T cells with the use of standard lymphodepletion regimens.

"These promising data show that both our Cloak and Dagger technology platforms can engineer AlloCAR T cells to minimize the potential of rejection by host immune cells, without impacting performance and in some cases, enhancing efficacy," said Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer of Allogene. "These innovative approaches are intended to simplify the lymphodepletion requirement for allogeneic CAR T products, and may provide a path to further expand the potential of off-the-shelf CAR T products beyond current targets and indications."

The Cloak platform technology is designed to prevent AlloCAR T cells from being recognized by host T cells without triggering substantial natural killer (NK) cell rejection while preserving CAR T cell function. Data shown previously demonstrated that knockout of RFX5, a transcriptional regulator that controls expression of HLA molecules, enhanced survival of allogeneic CAR T cells in the presence of host T cells and elicited only minor NK cell reactivity, thereby effectively mitigating rejection.

This preclinical study evaluated an additional anti-rejection approach to immune evasion by inactivating CD58 and ICAM-1, key components of the immune synapse required for effective recognition and lysis by alloreactive T/NK cells. In the study, the survival of "cloaked" cells was assessed in mixed lymphocyte reaction assays with T cells and NK cells. The knockout of CD58 and ICAM-1 effectively reduced T cell rejection of allogeneic CAR T cells without triggering NK cell rejection or impacting effector function and worked additively with the knockout of RFX5.

The Dagger platform technology arms AlloCAR T cells with a CD70 CAR designed to recognize and deplete CD70-positive host immune cells while enabling tumor-targeting anti-CD19 AlloCAR T cells to resist rejection from the host immune cells. This endows the CAR-expressing T cells with dual specificity against tumors that co-express CD19 and CD70, which includes approximately 70% of patients with large B-cell lymphoma (LBCL). As a result, this potential advance provides both a prolonged window of persistence during which AlloCAR T cells can expand and actively target and destroy cancer cells as well as insure against CD19 loss-mediated tumor escape, a known mechanism of resistance to CD19 CAR T therapy.

The Dagger technology, a feature of our ALLO-316 candidate, has clinically demonstrated its unique immunomodulatory effect, contributing to robust AlloCAR T cell expansion and persistence even with relatively lower doses of CAR T cells and lymphodepletion than in other AlloCAR T programs. The ongoing Phase 1 dose escalation TRAVERSE study using investigational ALLO-316 in patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed on standard therapies including an immune checkpoint inhibitor and a VEGF-targeting therapy.

Allogene Therapeutics Presents Preclinical Data on a Novel Allogeneic CAR T Product Candidate Targeting Claudin18.2 at the Society for Immunotherapy of Cancer Annual Meeting

On November 3, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported preclinical data on a novel off-the-shelf AlloCAR T product candidate targeting Claudin18.2 (CLDN18.2)-positive gastric and pancreatic tumors, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023, in San Diego, CA (Press release, Allogene, NOV 3, 2023, View Source [SID1234636876]).

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Data presented at SITC (Free SITC Whitepaper) describes preclinical development of Allogene’s novel allogeneic CLDN18.2 CAR T product candidate with the potential to provide clinical benefit to patients with a single, off-the-shelf infusion. CLDN18.2 has emerged as a promising therapeutic target, with high expression in many types of epithelial tumors including gastric, esophageal, pancreatic and ovarian cancers.

"Proof of concept for a CAR T targeting Claudin18.2 has been established, but limitations of autologous therapies, including the need for leukapheresis, long manufacturing wait times in patients with recent chemotherapy exposure, and high tumor and comorbidity burdens, would likely restrict availability to patients," said Zachary Roberts, M.D., Ph.D., Executive Vice President of Research & Development and Chief Medical Officer of Allogene. "An allogeneic product, derived from healthy donors and readily available to patients at the time of progression has the potential to overcome such challenges. We believe these preclinical data support a pathway to targeting CLDN18.2-positive solid tumors with an AlloCAR T product. This preclinical research further elucidates the depth of opportunity for our solid tumor program, and the potential to bring one of the most exciting modalities in modern times to patients in need."

The preclinical evaluation identified candidates with potent activity in both short-term and repeat stimulation in vitro cytotoxicity assays. The lead IND candidates researched displayed robust antitumor activity at low cell doses in vivo against both subcutaneous and intraperitoneal gastric cancer models. Data suggest the existence of a therapeutic window and the potential to target CLDN18.2 with allogeneic off-the-shelf CAR T cells without significant off tumor toxicity. These data were the foundation for ALLO-182, currently in the IND-enabling phase of development. ALLO-182 together with ALLO-213, an allogeneic CAR T targeting DLL3, represent the company’s early-stage solid tumor product candidates.

Alligator Bioscience Announces Poster Presentation on Neo-X-Prime Bispecific Antibody ATOR-4066 at SITC Annual Meeting 2023

On November 3, 2023 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported a poster presentation on ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, at the 2023 SITC (Free SITC Whitepaper) (Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)) Annual Meeting, being held in San Diego November 1-5, 2023 (Press release, Alligator Bioscience, NOV 3, 2023, View Source [SID1234636874]).

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The presentation, entitled "Combination treatment with ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, and anti-PD-1 reverses T cell exhaustion in vitro", outlines the use of CEACAM5 expressing tumor models to study the anti-tumor efficacy of ATOR-4066 and to analyze induction of immunological memory in vivo.

The presentation highlights that:

ATOR-4066 has a superior anti-tumor effect compared to a CD40 monospecific antibody
ATOR-4066 activation of CD40 expressing cells is CEACAM5-conditional with no activation in absence of CEACAM5 indicating a potential for a wide therapeutic window
ATOR-4066 is well positioned, with distinct advantages compared to other CD40 or CEACAM5 targeting therapies, such as strong anti-tumor effect in vivo also in larger tumors with heterogenous CEACAM5 expression
ATOR-4066 induces immunological memory in vivo and were able to clear homologous tumors upon re-challenge
Combining ATOR-4066 with anti-PD-1 in vitro in a mixed lymphocyte reaction assay[1] produces a clear synergistic effect observed on reactivation of exhausted T cells as measured by an increase in interferon gamma production
Using dissociated tumor cells from gastric cancer patients, ATOR-4066 induced activation of multiple tumor infiltrating immune cell populations (i.e. B cells, macrophages and T cells)
"To have this abstract accepted for presentation at this year’s prestigious SITC (Free SITC Whitepaper) annual meeting is a testament both to the promise of ATOR-4066 and to the diligent work of the Alligator scientific team," said Søren Bregenholt, CEO of Alligator Bioscience. "These data emphasize the potential of ATOR-4066 both as a monotherapy and as a combination partner for checkpoint inhibitors to further enhance the immune response in tumors and we continue to advance ATOR-4066 towards the clinic."

Poster Presentation Details
Abstract Number: 837
Title: Combination treatment with ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, and anti-PD-1 reverses T cell exhaustion in vitro
Date/Time: Friday 3 November, 2023, 9.00 am – 7.00 pm PDT
Presenter: Ida Uddbäck, Scientist, Alligator Bioscience
Location: Exhibit Halls A and B1, San Diego Convention Center

[1] Mixed lymphocyte reaction (MLR) – a common method for assessing the cellular immune response.

Adagene Presents Data Demonstrating the Best-in-Class Therapeutic Index for Masked Anti-CTLA-4 SAFEbody® ADG126 at SITC 2023

ON November 3, 2023 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported new data on its masked, anti-CTLA-4 SAFEbody ADG126 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting taking place in San Diego (Press release, Adagene, NOV 3, 2023, View Source [SID1234636873]). The poster presentation, Optimal Dose Selection of ADG126 (Masked Anti-CTLA-4 SAFEbody) with Significantly Widened Therapeutic Index Compared to Ipilimumab in Combination with anti-PD-1 Antibodies Informed by QSP Modeling, is available on the company’s website.

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The data, which integrate clinical results with physiologically based pharmacokinetic and quantitative systems pharmacology modeling, demonstrated that Adagene’s lead SAFEbody candidate, ADG126, is effective at targeting CTLA-4 within the tumor microenvironment (TME). This resulted in an approximately 30-fold projected pharmacokinetic difference at 10 mg/kg every three weeks (Q3W) in the TME indicating a wider therapeutic index (TI) compared to ipilimumab at 1 mg/kg Q6W, when either is combined with anti-PD-1 therapies.

The enhanced TI of ADG126 enables higher, more frequent and repeat dosing of ADG126 in combination with anti-PD-1, resulting in significantly increased CTLA-4 engagement by activated ADG126 at steady state in tumors versus circulating blood. Analyses also demonstrated that the optimal dose of ADG126 at 10 mg/kg Q3W plus pembrolizumab results in a dose-dependent efficacy profile, without a significant increase in treatment related adverse events (TRAEs).

Importantly, a clinical case example presented for the first time from an ongoing dose expansion cohort in advanced/metastatic MSS CRC* patients free of liver metastases showed that ADG126 10 mg/kg Q3W plus pembrolizumab resulted in a confirmed PR after four cycles (i.e., 12 weeks). The patient was previously treated with two lines of therapy (bevacizumab plus FOLFOX; aflibercept plus FOLFIRI) and experienced manageable Grade 3 TRAEs consistent with known adverse events from immunotherapy.

The poster concluded that initial clinical data from the SAFEbody ADG126 program support that ADG126 may provide greater clinical benefit than ipilimumab in combination with anti-PD-1 in both ‘hot’ and ‘cold’ tumors, including MSS CRC, driven by better target engagement in the TME and a favorable safety profile that enables higher, more frequent and repeat dosing.

ADG126 SAFEbody is the most advanced clinical stage anti-CTLA-4 candidate integrating masking technology and Treg depletion for superior safety and efficacy profiles. A phase 2 dose expansion cohort is ongoing to evaluate ADG126 plus pembrolizumab in patients with MSS CRC without liver metastases.

About ADG126 & SAFEbody Technology

SAFEbody technology is designed to address safety and tolerability challenges of antibody therapeutics by minimizing on-target off-tumor toxicity in healthy tissues. ADG126 is a masked anti-CTLA-4 therapy that applies the SAFEbody precision-masking technology to its parental antibody, ADG116, for conditional activation in the TME to expand the therapeutic index by addressing dose dependent toxicity issues that severely limit the dosage and dosing cycles for effective anti-CTLA-4 therapies.

Binding to the same distinct and highly conserved epitope as ADG116, the masked ADG126 is designed to provide enhanced safety and efficacy profiles due to the combination of the potent Treg depletion in the TME and partial ligand blocking by the activated ADG126, which is accumulated steadily for the prolonged tumor killing effect.

Clinical results together with detailed pharmacokinetic analyses support the unique mechanism of action for ADG126 and its profile as a potential best-in-class anti-CTLA-4 therapy.

* Microsatellite stable colorectal cancer (MSS CRC) accounts for approximately 95% of metastatic colorectal cancer patients. MSS tumors are referred to as ‘cold’ tumors, which means they don’t typically trigger a strong response from the body’s immune system. There is no currently approved immune-oncology treatment for MSS CRC.