On October 14, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported the initial safety, pharmacokinetics and recommended Phase 2 dose (RP2D) in the RAMP 203 trial evaluating the safety, tolerability and efficacy of avutometinib in combination with sotorasib in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) (Press release, Verastem, OCT 14, 2023, View Source [SID1234635977]). The results will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) October 11-15, 2023 in Boston, Massachusetts.

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"The RAMP 203 study is investigating the potential benefits of a more complete vertical blockade of the RAS pathway with the combination of avutometinib and sotorasib in KRAS G12C-mutant locally advanced or metastatic NSCLC," said Mark Awad, M.D., Associate Professor of Medicine at Harvard Medical School and Director of Clinical Research of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, investigator on the trial, and presenting author. "These initial findings, including the recommended Phase 2 dose and the encouraging preliminary efficacy and safety results, provide support for the combination, and I look forward to completing the expansion phase of the trial."

RAMP 203 (NCT05074810) is a Phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib + sotorasib in patients with KRAS G12C-mutant NSCLC who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor. The confirmed objective response rate (ORR) was 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%; 1/7) and naïve (40%; 2/5) patients.

The pharmacokinetic profile of avutometinib in combination with sotorasib was similar to results in monotherapy studies. No drug-drug interactions were observed between avutometinib and sotorasib. Avutometinib 4.0 mg PO BIW 21/28 days + sotorasib 960 mg PO QD 28/28 days was selected as RP2D based on dose limiting toxicity (DLT) assessment. Enrollment of patients with KRAS G12C-mutant NSCLC who are either naïve to or previously treated with a KRAS G12C inhibitor is ongoing in the expansion phase of RAMP 203.

"The RAMP 203 trial builds on preclinical data which demonstrated the addition of avutometinib to sotorasib improved the depth of MAPK pathway inhibition and substantially enhanced tumor regression relative to sotorasib alone," said Dan Paterson, President and CEO, Verastem Oncology. "Given KRAS G12C mutations are the most common KRAS mutation in NSCLC and acquired mutations and amplifications occur upon clinical progression to KRAS G12C inhibitor monotherapy, the results of the RAMP 203 trial are important in understanding potential new treatment approaches for patients."

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF, and CRAF potentially creating a more complete and durable anti-tumor response through increased RAS pathway inhibition. In contrast to currently available MEK inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The U.S. Food and Drug Administration granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, its FAK inhibitor, for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its Raf And Mek Program (RAMP). RAMP 301 is a Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation. Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant-NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205, a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

On October 14, 2023 Coherus BioSciences, Inc. ("Coherus", Nasdaq: CHRS), reported a presentation of toripalimab data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held October 11-15, 2023 at the Hynes Convention Center in Boston (Press release, Coherus Biosciences, OCT 14, 2023, View Source [SID1234635971]).

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PD-L1, a protein found on the surface of some cancer cells, suppresses T cell activation and inhibits the ability of the body’s immune system to kill cancer cells. Toripalimab is an anti-PD-1 monoclonal antibody that binds with high affinity to a unique site on PD-1, thereby blocking the interaction of PD-1 and PD-L1. Preclinical mechanistic data demonstrate statistically significantly higher activation of T cells and higher expression of key immune system activators with toripalimab compared to pembrolizumab, clinically a widely used anti-PD-1 monoclonal antibody for the treatment of cancer patients. These data may provide a mechanistic explanation for the improvements in overall survival irrespective of PD-L1 expression levels observed in clinical trials in multiple tumor types evaluating toripalimab in combination with chemotherapy. A biologics license application (BLA) for toripalimab in combination with chemotherapy as treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC) is currently under review by the U.S. Food and Drug Administration (FDA).

"PD-1 inhibition has been a significant advancement in cancer treatment across tumor types but better treatments are needed to increase response rates and drive improved outcomes for patients. These data support toripalimab as a next-generation PD-1 inhibitor that, in combination with chemotherapy, may have greater antitumor activity in less inflamed tumors than more commonly used PD-1 inhibitors in certain cancers due to its unique binding properties," said Theresa LaVallee, Ph.D., Coherus’ chief development officer. "We look forward to delivering this important new treatment option to patients, first in NPC, if approved, and continuing to evaluate its efficacy in combination with chemotherapy in multiple cancer types and in combination with novel I-O agents."

Poster presentation data are summarized as follows:

Toripalimab in combination with chemotherapy significantly improved overall survival irrespective of PD-L1 status in post hoc analyses of 3 randomized controlled clinical trials, including in NPC, non-small cell lung cancer (NSCLC) and esophageal squamous-cell carcinoma (ESCC)
Toripalimab exhibits a 12-fold higher binding affinity for PD-1 compared to pembrolizumab that is driven by a slow-off rate
Toripalimab is more potent than pembrolizumab in enhancing levels of Th1 cytokines and cytotoxicity in human peripheral blood mononuclear cells (PBMCs)
In comparison to pembrolizumab, binding of toripalimab to PD-1 induced low levels of SHP1 and SHP2 recruitment, thereby minimizing a key process of T cell suppression
Toripalimab induced and elevated IFN-y gene signature in NSCLC dissociated tumor cells with different kinetics and intensity compared to pembrolizumab
Poster presentation details:

Poster Number C069: Toripalimab, an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status
Session: Poster Session C
Date and time: Saturday, October 14, 12:30 pm-4:00 pm EDT
Location: Level 2, Exhibit Hall D
About toripalimab
Toripalimab is a next-generation anti-PD-1 monoclonal antibody that blocks PD-L1 binding to the PD⁠-⁠1 receptor at a unique site with high affinity and activates antitumor immunity demonstrating improvement in the overall survival of cancer patients in several tumor types. The BLA for toripalimab in combination with chemotherapy as the first-line treatment for recurrent or metastatic NPC and toripalimab monotherapy for the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy is under review by the FDA. In Europe, the marketing authorization applications (MAA) for toripalimab for the first-line treatment of NPC and esophageal squamous cell carcinoma (ESCC) are under review by the European Medicines Agency (EMA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).

The FDA granted Breakthrough Therapy designation for toripalimab in combination with chemotherapy for the first-line treatment of recurrent or metastatic NPC in 2021 as well as for toripalimab monotherapy in the second or third-line treatment of recurrent or metastatic NPC in 2020. Additionally, the FDA has granted Fast Track designation for toripalimab for the treatment of mucosal melanoma and Orphan Drug designations for the treatment of ESCC, NPC, mucosal melanoma, soft tissue sarcoma, and small-cell lung cancer (SCLC).

More than 40 company-sponsored toripalimab clinical studies covering over fifteen indications have been conducted globally by Shanghai Junshi Biosciences Co., Ltd (Junshi Biosciences), including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin.

On October 14, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from the Company’s next-generation selective fibroblast growth factor receptor 2 (FGFR2) program being presented today in a poster presentation at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) taking place in Boston (Press release, Cogent Biosciences, OCT 14, 2023, View Source [SID1234635970]).

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"We are excited to share these new data on our internally discovered and developed FGFR2 candidate, highlighting the strength and scientific expertise of the Cogent Research Team," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "We believe CGT4859 has the potential to become the best-in-class FGFR2 inhibitor, as it delivers coverage across all known resistance mutations, with selectivity to avoid FGFR1-mediated toxicity, along with a reversible profile which may improve upon tolerability challenges seen with other FGFR2-targeted agents. IND-enabling studies for CGT4859 are ongoing, putting us in position to initiate clinical trials in the second half of 2024."

Poster Details
The poster can be accessed in the ‘Posters and Publications’ page of Cogent’s website.

Title: Identification of a Reversible Selective FGFR2 Clinical Development Candidate with Potency Against Gatekeeper and Molecular Brake Mutations
Session: Poster Session C
Session Date and Time: Saturday, October 14, 2023 – 12:30 PM – 4:00 PM ET
Location: Level 2, Exhibit Hall D, Hynes Convention Center, Boston, MA
Poster Number: C161
Abstract Number: 35488

FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today describes Cogent’s internally-developed FGFR2 inhibitor which exhibits low nM potency on WT FGFR2 and FGFR2 mutations and is selective against the kinome and a panel of channels and receptors. Exploratory pharmacokinetics (PK) studies conducted across species showed CGT4859 to be a low-clearance compound with high oral bioavailability. Further, in an AN3 CA model, CGT4859 demonstrated dose-responsive tumor growth inhibition with complete regressions at 5 mg/kg PO and was well-tolerated. Cogent plans to file an IND, and pending clearance from the FDA, initiate clinical trials in 2024.

On October 14, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported results demonstrating encouraging response durability of BDTX-1535 in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, Black Diamond Therapeutics, OCT 14, 2023, View Source [SID1234635969]). BDTX-1535, a fourth-generation, brain-penetrant epidermal growth factor receptor (EGFR) inhibitor, is under investigation in a Phase 1 clinical trial for patients with NSCLC or glioblastoma multiforme (GBM). The NSCLC results were disclosed in a poster presentation on October 14, 2023 at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston.

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The findings expand upon the initial dose escalation results disclosed on June 27, 2023, which showed anti-tumor activity of BDTX-1535 in patients with NSCLC across heterogeneous EGFR mutation subtypes (including acquired resistance C797S mutation, intrinsic driver mutations, e.g., L747P, L718Q, as well as complex mutations). Data shared at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC conference reflects 27 patients with advanced/metastatic NSCLC who received a range of doses spanning 25mg to 400mg once daily. A poster titled "Phase 1 Study of BDTX-1535, an Oral 4th Generation Inhibitor, in Patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary Dose Escalation Results" shows that BDTX-1535 achieved:

Drug exposures providing target coverage. Pharmacokinetic (PK) analyses demonstrated that doses at or above 100mg provide sufficient drug levels to cover all relevant mutations over a 24-hour period following once daily oral administration.
Favorable emerging safety profile. The majority of adverse events (AEs) at doses of 100mg and 200mg were mild or moderate, and no unexpected safety signals were identified. No dose limiting toxicities (DLTs) were observed at or below 200mg dose level.
Circulating tumor DNA (ctDNA) clearance. Eradication of targeted variant alleles and significant ctDNA reductions were observed for all NSCLC EGFR mutation subtypes in patients treated across dose levels. ctDNA reduction has been shown to be predictive of clinical response.
Radiographic responses in patients with NSCLC at starting dose of 100mg or above. Five of the 13 patients with either intrinsic driver, acquired resistance or complex mutations had a confirmed partial response (PR) by RECIST1.1. One patient remains an unconfirmed PR and continues on study with no sign of tumor progression, and six patients have stable disease at doses at or above 100mg once daily. Evidence of reduction in brain metastases was observed, including a patient with more than three prior therapies.
Durable clinical responses in patients with NSCLC who have had multiple lines of prior therapy. Three responders continue on therapy for greater than six months (two confirmed PRs, one uPR). One patient with confirmed PR remained on therapy for six months. Two additional patients with stable disease continue on therapy for greater than 12 months.
"These results point to a highly active compound that has the potential to fill a substantial unmet need for an oral, well-tolerated precision therapy option in the current NSCLC therapeutic landscape for patients who progressed on a third-generation EGFR inhibitor," said Helena Yu, M.D., Associate Attending Physician at Memorial Sloan Kettering Cancer Center. "We are most encouraged by the durable responses observed, as they underscore the potential of BDTX-1535 for patients with NSCLC who have progressed on prior tyrosine kinase inhibitors (TKIs)."

Black Diamond is currently enrolling patients in the expansion cohorts evaluating BDTX-1535 at doses of 100mg and 200mg in patients with intrinsic driver and acquired resistance EGFR mutation positive NSCLC assessing objective response rate (ORR) by RECIST 1.1. The Company expects to share initial results from this portion of the study in 2024.

"These dose escalation results underscore that the well-tolerated and durable clinical activity of BDTX-1535 could have important implications for patients with EGFR mutant NSCLC," said Sergey Yurasov, M.D., Ph.D., Chief Medical Officer of Black Diamond Therapeutics. "As real-world evidence shows, C797S is the most prevalent on-target resistance mutation, co-occurring with an increasingly heterogeneous set of other EGFR-acquired resistance mutations, intrinsic drivers, and classical drivers, highlighting the need for an agent like BDTX-1535 to address the complex combination of mutations. We look forward to results from the dose expansion cohorts in patients with NSCLC in 2024 and our End of Phase 1 meeting with the FDA later this year."

Black Diamond also presented two additional posters outlining the study design of the ongoing Phase 1 clinical trial of BDTX-1535 in NSCLC and preclinical data for BDTX-4933, a brain-penetrant MasterKey RAF inhibitor targeting KRAS, NRAS and BRAF alterations in solid tumors. Key preclinical findings from the BDTX-4933 presentation include:

BDTX-4933 potently and selectively inhibited the proliferation of tumor cells expressing a range of KRAS, NRAS and BRAF mutations in cell lines, suggesting potential best-in-class potency compared to other RAF inhibitors.
BDTX-4933 demonstrated strong anti-tumor activity and regression across cell line and patient-derived xenograft models expressing several MAPK pathway mutations, including KRAS G12D, KRAS G12V, and KRAS G13C mutant NSCLC models.
BDTX-4933 exhibited high central nervous system (CNS) exposure leading to dose-dependent tumor growth inhibition and survival benefit in mice implanted intracranially with xenograft BRAF mutant tumors.
Black Diamond initiated a Phase 1 clinical trial for BDTX-4933 with emphasis on KRAS mutant NSCLC in the second quarter of 2023.

About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC), including families of intrinsic driver mutations (e.g., L747P, L718Q), acquired resistance C797S mutation, and complex mutations. BDTX-1535 is a fourth-generation TKI that potently inhibits, based on preclinical data, greater than 50 oncogenic EGFR mutations and alterations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma multiforme (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. The ongoing BDTX-1535 Phase 1 clinical trial is currently in dose expansion for NSCLC and dose escalation for GBM (NCT05256290).

About BDTX-4933
BDTX-4933 is an oral, brain-penetrant RAF MasterKey inhibitor designed to target oncogenic alterations in KRAS, NRAS and BRAF, while also avoiding paradoxical activation. In preclinical studies, BDTX-4933 has demonstrated a potential best-in-class profile, showing potent target engagement, inhibition of MAPK signaling and strong anti-tumor activity/tumor regression across tumor models driven by either KRAS, NRAS or BRAF mutations and alterations. BDTX-4933 also exhibits high central nervous system (CNS) exposure leading to dose-dependent tumor growth inhibition and a survival benefit in an intracranial tumor model harboring oncogenic BRAF mutation. The ongoing BDTX-4933 Phase 1 clinical trial is currently in dose escalation with emphasis on KRAS mutant NSCLC patients (NCT05786924).

On October 14, 2023 Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through the development of potentially best-in-class IL-2 therapeutics, reported new pharmacodynamic data from the ongoing Phase 1 dose escalation portion of its Phase 1/2 clinical trial of AU-007, the first human monoclonal antibody designed using artificial intelligence to be tested in a clinical trial (Press release, Aulos Bioscience, OCT 14, 2023, View Source [SID1234635968]). The data were shared in a poster presentation at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston, Massachusetts.

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The study evaluated AU-007 as a monotherapy treatment or in a combination therapy regimen with low-dose subcutaneous Proleukin (aldesleukin; recombinant human IL-2). The data demonstrate that AU-007 redirects interleukin-2 (IL-2) from regulatory T cells (Tregs) toward effector T cells (Teffs) and natural killer (NK) cells, which can kill tumor cells. The data also show a reduction in eosinophils, which at high cell counts can be associated with toxicity in the lungs.

"We believe AU-007 may be therapeutically effective in solid tumor cancers, and the cell types of interest in this study are trending in the right directions," said Aron Knickerbocker, Aulos Bioscience’s chief executive officer. "These data continue to demonstrate favorable and unique pharmacodynamic effects in the IL-2 class. When AU-007 is administered to patients as monotherapy or in combination with low doses of Proleukin, the data show a decrease in immunosuppressive Tregs and increases in the numbers of Teffs and NK cells, both of which are cell types capable of killing tumor cells. To our knowledge, no other IL-2 therapy has shown such a profile of immune cell changes and the resulting change in the ratio of effector to suppressor immune cells. We also observed immune activation as assessed by interferon-gamma levels, which tend to increase following AU-007 with Proleukin. We will share the results of further pharmacodynamic investigations of AU-007 in combination with higher doses of Proleukin in the future. We also look forward to presenting new clinical efficacy and safety data from the Phase 1 dose escalation cohorts later this year."

Created by Biolojic Design, AU-007 is a human IgG1 monoclonal antibody designed using artificial intelligence to harness the power of IL-2 to eradicate solid tumors. The antibody’s novel mechanism of action lies in its ability to bind precisely to IL-2 instead of IL-2 receptors. By binding only to the portion of IL-2 that binds to CD25, AU-007 prevents IL-2 from binding to high-affinity IL-2 receptors on Tregs and eosinophils and redirects IL-2 to medium-affinity receptors on NK cells and effector T cells. This allows effector T cells and NK cells to expand and kill tumor cells.

The Phase 1 dose escalation study presented at the AACR (Free AACR Whitepaper)-NCI-EORTC International Conference shows that AU-007 redirected IL-2 from Tregs toward effector T cells and NK cells and expanded those cells with and without low doses of Proleukin, which is consistent with the antibody’s mechanism of action. This overall effect increased with time on Proleukin given every two weeks with AU-007, or with higher dose levels of Proleukin. These changes were observed across a broad range of cancer types and were not associated with any drug-related events. Additionally, AU-007 treatment led to decreases in eosinophils and increases in interferon-gamma with and without Proleukin, which supports the antibody’s proposed activity.

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 site locations in the United States and Australia. The company anticipates transitioning to the Phase 2 portion of the AU-007 study by year-end.

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

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 vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy.