On April 10, 2021 Blueprint Medicines Corporation (NASDAQ: BPMC) reported data from multiple poster presentations highlighting the breadth of the company’s precision therapy pipeline at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Blueprint Medicines, APR 10, 2021, View Source [SID1234577850]). Collectively, the presentations, including foundational preclinical data for multiple programs, demonstrate the productivity of the company’s scientific platform. Additional presentations of clinical data for AYVAKIT (avapritinib) and BLU-263 will be reported on Sunday, April 11, 2021.

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"Our data presentations at the AACR (Free AACR Whitepaper) annual meeting showcase Blueprint Medicines’ next wave of precision therapies, which have the potential to impact large global patient populations," said Fouad Namouni, M.D., President, Research & Development at Blueprint Medicines. "Building on the foundation of our approved medicines AYVAKIT and GAVRETO, these presentations highlight our efforts to address significant patient needs in areas such as EGFR-driven lung cancer, cyclin E-aberrant cancers and cancer immunotherapy. As we celebrate our 10th anniversary as a company, and our rapidly expanding pipeline now includes our ninth development candidate, we look forward to continuing to leverage our productive research platform to advance potent and selective inhibitors that have the potential to enable transformative benefit for patients."

BLU-701 and BLU-945: Double- and triple-mutant inhibitors in EGFR-driven NSCLC

Lung cancer is the leading cause of cancer death globally, and approximately 17 percent of patients with lung adenocarcinoma, the most common form of non-small cell lung cancer (NSCLC), have EGFR-driven disease. While first- and third-generation EGFR inhibitors have improved treatment outcomes for patients with EGFR-driven NSCLC, resistance inevitably emerges, with the T790M and C797S mutations being the most common on-target resistance mechanisms. Together, BLU-701 and BLU-945 are designed to provide comprehensive coverage of the most common activating and on-target resistance mutations, spare wild-type EGFR to limit toxicities driven by wild-type EGFR inhibition and treat or prevent central nervous system (CNS) metastases. Ultimately, with these characteristics, BLU-701 and BLU-945 have the potential to be used either as monotherapy or in combination, together or with other agents, to potentially overcome or prevent on-target resistance across multiple lines of treatment.

BLU-701 is a potential best-in-class, selective, potent, fourth-generation double-mutant EGFR inhibitor with activity against EGFR activating mutations and the C797S osimertinib-resistant mutation. Preclinical data presented at the conference showed strong and durable inhibition of tumor growth at doses that are EGFR wild-type sparing. BLU-701 also indicated significant CNS penetration in preclinical models, with comparable exposure in the plasma and brain, which illustrates its potential to treat or prevent CNS metastases in patients with EGFR-driven tumors. With activity also shown against the activating EGFR mutants, BLU-701 has potential to be used in both first- and second-line settings.

BLU-945 is a potential first- and best-in-class, selective, potent, fourth-generation triple-mutant EGFR inhibitor with activity against the T790M and C797S resistance mutations. BLU-945 is highly selective over wild-type EGFR and off-target kinases, highlighting its potential to enable tolerable combinations with BLU-701 or other therapies. Data presented at the conference demonstrated potent anti-tumor activity in triple-mutant osimertinib-resistant tumor models, as well as activity in a triple-mutant intracranial patient-derived xenograft model. In addition, the combination of BLU-945 with either gefitinib or osimertinib showed enhanced anti-tumor activity when compared with either gefitinib or osimertinib alone.

The preclinical data presented for BLU-701 and BLU-945 support the continued development of both candidates in patients with EGFR-driven NSCLC. An investigational new drug (IND) application for BLU-945 has been cleared by the U.S. Food and Drug Administration (FDA) and an international Phase 1 dose escalation trial is expected to begin this quarter. Future clinical development of BLU-945 in combination with other agents across multiple treatment settings is planned. BLU-701 is expected to enter clinical development later this year.

BLU-222: CDK2 inhibitor in cyclin E-aberrant cancers

Cyclin dependent kinases (CDKs) and their cyclin partners regulate the cell cycle. In subsets of patients across multiple cancer types, aberrant cyclin E (CCNE) hyperactivates CDK2, resulting in cell cycle dysregulation and tumor proliferation. Aberrant CCNE has been observed as a primary driver of disease as well as a mechanism of resistance to CDK4/6 inhibitors and other therapies. In addition, data have shown that ovarian and hormone-receptor-positive breast cancer patients with aberrant CCNE have poor outcomes. Prior drug discovery efforts targeting CDK2 have been hindered by challenges in achieving selectivity over other CDK family members associated with toxicity.

At AACR (Free AACR Whitepaper), preclinical data highlighted a set of potent and selective CDK2 inhibitors designed by Blueprint Medicines. The data showed that selective CDK2 inhibition arrested the cell cycle and blocked tumor proliferation in CCNE-amplified cell lines and demonstrated robust and sustained anti-tumor activity in vivo in models of CCNE-amplified ovarian, breast and gastric cancer. A selective CDK2 inhibitor also showed improved tolerability compared to a pan-CDK inhibitor and chemotherapy, as measured by animal body weight.

Based on this work and further optimization, Blueprint Medicines reported the nomination of a potentially best-in-class selective and potent CDK2 inhibitor development candidate, BLU-222, which is expected to enter clinical development in the first half of 2022.

BLU-852: MAP4K1 inhibitor

MAP4K1 is a well-characterized immunokinase target involved in the regulation of immune cells; however, prior drug discovery efforts have been hindered by challenges in achieving selectivity over other MAP4K family members associated with toxicity. In January 2021, Blueprint Medicines announced the nomination of a highly selective and potent MAP4K1 inhibitor development candidate, BLU-852, with best-in-class potential.

Data presented at AACR (Free AACR Whitepaper) highlighted a set of potent and highly selective MAP4K1 inhibitors designed by Blueprint Medicines, including BLU-852. The inhibitors were shown to enhance intratumoral immune cell activation, overcome T cell suppression, and reduce tumor burden both as a monotherapy and in combination with checkpoint inhibition. The data support the continued development of BLU-852 under the company’s cancer immunotherapy collaboration with Roche, with Phase 1 trial initiation anticipated in 2022.

Copies of Blueprint Medicines data presentations from the AACR (Free AACR Whitepaper) annual meeting are available in the "Science—Publications and Presentations" section of the company’s website at www.BlueprintMedicines.com.

Conference Call Information

Blueprint Medicines will host a live webcast on Monday, April 12, 2021 beginning at 8:00 a.m. ET to review data for multiple research- and clinical-stage programs presented at the AACR (Free AACR Whitepaper) annual meeting. To access the live call, please dial (855) 728-4793 (domestic) or (503) 343-6666 (international) and refer to conference ID 5548976. A webcast of the conference call will be available under "Events and Presentations" in the Investors & Media section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

On April 10, 2021 Arcus Biosciences, Inc. (NYSE:RCUS), an oncology-focused biopharmaceutical company working to create best-in-class cancer therapies, today presented progression-free survival (PFS) and overall survival (OS) data in patients with advanced metastatic colorectal cancer (mCRC) from the ARC-3 study at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Arcus Biosciences, APR 10, 2021, View Source [SID1234577866]). ARC-3 was a Phase 1/1b, multicenter, open-label, dose-escalation and dose-expansion study that evaluated the safety, tolerability, PK and early clinical activity of etrumadenant, the first dual adenosine A2a/A2b receptor antagonist in the clinic, in subjects with mCRC.

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Additionally, Arcus presented details of its Hypoxia-Inducible Factor 2α (HIF-2α) research program, including the design of a novel series of HIF-2α inhibitors, which has resulted in the identification of molecules such as AB521, with excellent potency, selectivity, biological activity and pharmacokinetic properties suitable for further development.

ARC-3: Updated Results of Etrumadenant (AB928) + mFOLFOX-6 in Patients with Metastatic Colorectal Cancer

Initial results from ARC-3 demonstrated that etrumadenant + modified FOLFOX-6 (mFOLFOX-6) in patients with mCRC was well tolerated and associated with a substantial disease control rate (DCR) across all lines of therapy, including in patients with microsatellite stable disease and RAS/BRAF-mutated mCRC1,2.

Updated data from the 3L+ cohort (median of 3 and a range of 2 to 7 prior lines), in which 87% of the patients had received prior FOLFOX, demonstrated the following:

Safety Results (n=23 safety-evaluable 3L+ patients as of the DCO of Feb. 26, 2021)
Etrumadenant + mFOLFOX-6 was well tolerated, and etrumadenant, at the evaluated doses of 75mg and 150mg once daily (QD), did not appear to add significant toxicity to that expected for mFOLFOX-6.
No grade 3 or above neuropathy events were observed in this heavily pretreated population.
The most common treatment emergent adverse events (TEAEs) for the etrumadement- mFOLFOX-3 combination were fatigue (70%), thrombocytopenia (57%), diarrhea (52%) and nausea (52%).
Efficacy Results (n=22 efficacy-evaluable 3L+ patients as of the DCO of Feb. 26, 2021)
Median progression-free survival (PFS) of 4.2 months. Reported data for current standard-of-care (SOC) therapies have shown a median PFS of 2.0 and 1.9 months for trifluridine-tipiracil and regorafenib, respectively3,4.
Median overall survival (OS) of 13.6 months. Reported data for trifluridine-tipiracil and regorafenib have shown a median OS of 7.1 and 6.4 months, respectively3,4.
Objective response rate (ORR) of 9.1% and an encouraging 8-week DCR of 86%. Reported data for trifluridine-tipiracil and regorafenib have shown ORRs of 1.6% and 1%, respectively 3,4.
Patients with higher tumor mutation burden and intra-tumoral expression of CD73 demonstrated improved outcomes compared to patients with lower levels of these biomarkers, consistent with previous findings1, which may be reflective of an etrumadenant-mediated effect.
"Based on these very encouraging early results, we have advanced etrumadenant into ARC-9, a randomized Phase 2 platform study to evaluate this first-in-class molecule in combination with zimberelimab, our anti-PD-1 antibody, and FOLFOX +/- bevacizumab in second- and third-line mCRC," said Bill Grossman, M.D., Ph.D., Chief Medical Officer of Arcus. "The results presented today, combined with our recent promising early data evaluating AB680, our small-molecule CD73 inhibitor, in pancreatic cancer, support an expanding rationale for targeting the ATP-adenosine axis to meet critical unmet needs in gastrointestinal cancers."

"Few options exist today to treat third-line colorectal cancer, and these therapies are associated with significant toxicity and limited efficacy. While this was an early-stage study, etrumadenant’s efficacy in this difficult-to-treat patient population was impressive, particularly the doubling of progression-free and overall survival that was observed relative to what has been reported for current standard-of-care therapies," said Michael Cecchini, MD, Assistant Professor of Medicine (Medical Oncology), Yale Cancer Center and Smilow Cancer Hospital. "Importantly, etrumadenant also added very little toxicity, enabling patients to remain on treatment for extended periods of time. I look forward to working with Arcus to advance etrumadenant, and Arcus’s other ATP-adenosine axis-targeting agents, into later-stage studies for gastrointestinal cancers in order to broaden access to these innovative potential therapies."

Preliminary data from ARC-9, a global follow-on study to ARC-3, are expected to be presented in the first half of 2022. For additional information on this trial, please visit NCT04660812, at www.clinicaltrials.gov.

Discovery and Characterization of AB521, a Novel, Potent, and Selective HIF-2 α Inhibitor

Preclinical and clinical evidence indicate that HIF-2α inhibition is a validated approach for the treatment of clear cell renal cell carcinoma (ccRCC) and tumors associated with mutant/deficient Von Hippel-Lindau (VHL). Arcus has developed a broad research program to identify drug candidates against this target. Despite the inherent difficulties in identifying drug-like inhibitors of HIF-2α, Arcus scientists have generated highly optimized inhibitors, including AB521, which exhibit high potency, selectivity and biological activity, as well as a favorable pharmacokinetic profile in preclinical species, that we expect will facilitate achieving optimal plasma levels of drug in the clinic.

We expect to initiate clinical development for our lead HIF-2α inhibitor in the second half of 2021 and plan to combine this molecule with other product candidates from our pipeline, including our first-in-class adenosine axis-targeting agents.

Additional information about these presentations may be found on the Arcus website at Arcus Publications.

About Etrumadenant

Etrumadenant (AB928), the first dual A2a/A2b adenosine receptor antagonist in the clinic, is designed to maximally inhibit the adenosine-driven impairment of tumor-infiltrating lymphocytes (mainly CD8+ T cells and NK cells) and myeloid cells (dendritic cells, macrophages), mediated by A2aR and A2bR, respectively. A2bR is also upregulated by certain cancer cells, such as in prostate cancer and KRAS- mutated cancers. As a result, etrumadenant may uniquely block adenosine’s immunosuppressive and cancer cell-intrinsic effects. Developed specifically for the oncology setting, etrumadenant achieves high penetration of tumor tissue, robust potency in the presence of high adenosine concentrations, and minimal shift in potency from non-specific protein binding. Etrumadenant has demonstrated a favorable safety profile with a variety of combination regimens and exhibits pharmacokinetics / pharmacodynamics consistent with once-daily dosing. AB928 is currently being evaluated in several Phase 1b/2 studies across multiple indications.

On April 10, 2021 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that a Phase 1b trial of GMI-1359, being conducted at Duke University Cancer Center, showed evidence of on-target effects, immune-activation and cell mobilization in the initial two patients treated with the Company’s dual antagonist of E-selectin and CXCR4 (Press release, GlycoMimetics, APR 10, 2021, View Source [SID1234577818]). Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine, will present results from the proof-of-concept clinical study as well as a separate preclinical study supporting the positive biologic findings of the Phase 1b study. The presentation will be made at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting, which is being held virtually on April 10-15 and May 17-21. GMI-1359 is GlycoMimetics’ novel small molecule drug candidate, a dual antagonist of E-selectin and CXCR4, designed to target tumor-microenvironment resistance to chemotherapy in cancers with bone metastases.

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The initial data from the study confirmed the dual CXCR4 and E-selectin antagonist’s on-target effects. In the two patients who completed treatment, evaluations of peripheral blood showed a consistent mobilization of CD34+ hematopoietic stem and progenitor cells at doses beginning at 5 mg/kg and a reduction of plasma levels of soluble E-selectin. Furthermore, in one individual, following the administration of 7.0 mg/kg of GMI-1359, an immunophenotyping assessment of peripheral blood showed a redistribution of myeloid derived suppressor cells (MDSCs) as evidenced by increased percentages of both the monocytic and granulocytic MDSCs. In this same individual following administration of 7.0 mg/kg GMI-1359, the incidence of M1 proinflammatory macrophages increased while the M2 anti-inflammatory macrophages, often associated with tumor progression, decreased. The clinical poster concludes that GMI-1359 demonstrated an acceptable safety and tolerability profile in the patients treated to date. No dose limiting toxicities were observed following multiple dose administration up to 7 mg/kg.

Dr. Sipkins noted, "Despite the fact that our patient numbers are very small due to COVID’s impact on recruitment, we are seeing the on-target effects of antagonizing both CXCR4 and E-selectin with use of GMI-1359, and that the drug is well-tolerated at all dose levels. Our pilot immune profile analysis also suggests that the drug could have favorable effects on the tumor immune microenvironment, echoing results seen in our preclinical work."

Dr. Sipkins will disclose preclinical evidence that it may be possible for GMI-1359 to augment immune recognition of the tumor. The data in the poster from a mouse metastatic breast carcinoma model demonstrated a reduction in the immune suppressive monocytic MDSCs at the primary tumor site and a significant increase in the CD8/Treg ratio in both the primary tumor and at the bone metastatic sites. These findings on immune cell redistributions strongly suggest the induction of a more favorable anti-tumor environment following GMI-1359 administration.

According to Dr. Eric J. Feldman, GlycoMimetics Senior Vice President and Chief Medical Officer, "The information shared in this AACR (Free AACR Whitepaper) poster provides us with important understandings upon which we expect to identify a potential indication for advancing GMI-1359 in the clinic. It suggests that this small molecule drug candidate could improve responses to therapies and potentially reduce the burden of metastatic breast cancer disease."

In prior preclinical research supported by GlycoMimetics, Dr. Sipkins’ laboratory demonstrated that E-selectin and CXCR4/SDF-1 interactions were critical for breast carcinoma cells (BCCs) invasion and retention, respectively, into bone. Moreover, they found that dormant and proliferating BCCs occupy distinct regions of the bone microenvironment, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions. These dormant BCCs are expected to be highly susceptible to GMI-1359 mobilization, suggesting a new intervention to break the foothold of dormant BC micrometastases in bone.

Details on the GMI-1359 e-presentation at the AACR (Free AACR Whitepaper) Meeting are as follows:

Title: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
Presenter: Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine
Session: e-Presentation
Date and Time: Saturday, April 10, 2021 (available online through Monday, June 21)

About GMI-1359

GMI-1359 is designed to simultaneously inhibit both E-selectin and CXCR4, which are adhesion molecules involved in tumor trafficking and metastatic spread. Preclinical studies indicate that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that involve the bone marrow, such as AML and multiple myeloma, or in solid tumors that metastasize to the bone, such as prostate cancer and breast cancer, as well as in osteosarcoma, a rare pediatric tumor affecting about 900 adolescents a year in the United States. GMI-1359 completed a Phase 1 clinical trial in healthy volunteers, and a Phase 1b clinical study is underway in breast cancer patients and is designed to enable investigators to identify study dose ranging and to generate initial biomarker data around the drug’s activity. In the first two patients evaluated, the study showed evidence of on-target effects, immune-activation and cell mobilization. GMI-1359 has received Orphan Drug designation and Rare Pediatric Disease designation from the FDA for the treatment of osteosarcoma.

On April 10, 2021 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, and Precision for Medicine, a specialized services company supporting next generation approaches to drug development and commercialization, reported data on the development of a novel flow immunophenotyping assay to accurately evaluate total PD-1 expression as a pharmacodynamic marker during PD-1 blockade, and translational data demonstrating immune responses correlated to observed clinical benefit from the Company’s ongoing Phase 1/2 study evaluating ADXS-503 in combination with KEYTRUDA, presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Advaxis, APR 10, 2021, View Source [SID1234577835]). ADXS-503 is the first drug construct from the ADXS-HOT off-the-shelf, cancer-type specific, immunotherapy program which leverages Advaxis’ proprietary Lm technology platform to target hotspot mutations that commonly occur in specific cancer types as well as other proprietary, tumor-associated antigens.

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"These presented data suggest this novel immunophenotyping assay has the potential to more accurately measure pharmacodynamic biomarkers in immunotherapy," said Ken Berlin, Chief Executive Officer of Advaxis. "This assay enables the detection of both free and drug-bound PD-1 expression, independent of PD-1 receptor status or interference due to PD-1 blockade, enabling the accurate evaluation of PD-1 expression in patients undergoing treatment with pembrolizumab. We believe this is another important step forward in further understanding immune responses in patients treated with immunotherapy agents, and may provide important translational insights specific to PD-1 expression and immune modulation which may help shape treatment strategies moving forward."

Mr. Berlin continued, "The flow cytometry data confirmed the on-mechanism activation of the innate and adaptive immune systems in patients with observed clinical benefit following treatment with ADXS-503 in combination with pembrolizumab. The demonstrated proliferation and activation of NK cells and CD8 + T cells, plus increased PD-1 expression in diverse immune cells in patients achieving clinical benefit, add to the growing body of evidence which demonstrate the potential of ADXS-503 to re-sensitize or enhance responses to pembrolizumab, even in patients with prior progression. We will continue these analyses with Precision for Medicine on additional patients from our ongoing Phase 1/2 study in NSCLC, and look forward to continued progress as we build upon our previously reported efficacy results which show promising and durable clinical benefit after treatment with ADXS-503, our first off-the-shelf neoantigen immunotherapy candidate."

Key presentation highlights:

Poster presentation titled, "Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets" presented by Dr.Venkat Mohanram, Senior Scientist at Precision for Medicine.

A novel multi-color flow cytometry analysis was developed to accurately identify PD-1 expression on peripheral blood mononuclear cells (PBMCs) of NSCLC patients receiving PD-1/PD-L1 blockade therapy with pembrolizumab and ADXS-503

No interference in PD-1 detection due to pembrolizumab blockage was observed, enabling the determination of PD-1 expression independent of PD-1 receptor status, with both free and drug-bound PD-1 detected

Preliminary flow cytometry data demonstrated on-mechanism activation of innate and adaptive immune responses to ADXS-503. Three patients from the ongoing Phase 1/2 with demonstrated clinical benefit of stable disease showed:

Proliferation and activation of NK cells
Increased PD-1 expression on circulating CD4+, CD8+ and NK cells
Increased counts of CD8+ T cells including proliferative, cytotoxic and memory CD8+ T cells
The Phase 1/2 clinical trial of ADXS-503 is seeking to establish the recommended dose, safety, tolerability and clinical activity of ADXS-503 administered alone and in combination with a KEYTRUDA in approximately 50 patients with NSCLC, in at least five sites across the U.S. The two dose levels with monotherapy in Part A, (1 X108 and 5 X108 CFU) have been completed. Part B with ADXS-503 (1 X108 CFU) in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 15 patients at dose level 1 (1 X108 CFU + KEYTRUDA) with the potential to proceed to dose level 2 (5 X108 CFU + KEYTRUDA) at a later date. Part C, which is evaluating ADXS-503 in combination with KEYTRUDA (1 X108 CFU + KEYTRUDA) as a first line treatment for patients with NSCLC with PD-L1 expression ≥ 1% or who are unfit for chemotherapy is currently enrolling patients.

About ADXS-HOT
ADXS-HOT is a program that leverages the Company’s proprietary Lm technology to target hotspot mutations that commonly occur in specific cancer types. ADXS-HOT drug candidates are designed to target acquired shared or "public" mutations in tumor driver genes along with other proprietary cancer-testes and oncofetal tumor-associated antigens that also commonly occur in specific cancer types. ADXS-HOT drug candidates are an off-the-shelf treatment, designed to potentially treat all patients with a specific cancer type, without the need for pretreatment biomarker testing, DNA sequencing or diagnostic testing.

On April 10, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, reported the availability of three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Harpoon Therapeutics, APR 10, 2021, View Source [SID1234577851]). The presentations will be available beginning today at 8:30 a.m. ET through the virtual meeting website at www.aacr.org and on the Harpoon corporate website at www.harpoontx.com.

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Key findings of each of the posters are described below.

FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia
Presenter: Richard J. Austin, Ph.D., Abstract #: 2643

FLT3 RNA is found in over 95% of AML samples and FLT3 mutations are oncogenic and found in approximately 30% of AML. This provides the rationale that a FLT3-targeting T cell engager could be a valid therapeutic approach for AML. Data show that FLT3 TriTACs bind human and non-human primate FLT3, and can redirect T cells to kill FLT3 expressing cells in vitro. In addition, FLT3 TriTACs eliminate FLT3 expressing cells in a non-human primate study and are well tolerated after a single dose.

ProTriTAC is a modular and robust T cell engager prodrug platform with therapeutic index expansion observed across multiple tumor targets
Presenter: S. Jack Lin, Ph.D., Abstract #: 933

ProTriTAC is a conditionally active T cell engager platform that is designed to be preferentially active in the tumor. This enables the targeting of more broadly expressed solid tumor targets and allows T cell engagers to address more tumor types. Data presented today illustrate the consistency and the robustness of the ProTriTAC platform in vitro and in vivo as demonstrated by cell-based assays, pharmacokinetic studies in non-human primates, and therapeutic index assessments in tumor-bearing animals across multiple tumor targets. IND-enabling studies are currently underway for Harpoon’s first ProTriTAC program (HPN601).

Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models
Presenter: Mary Ellen Molloy, Ph.D. Abstract #: 1573

TriTAC molecules induce PD1/PD-L1 expression on T cells which may lead to suppression of the cytolytic functions of TriTAC activated T cells. PD1 can be readily detected on T cells subsequent to the engagement of the TCR by the TriTAC molecule. Data presented today show that the combination of HPN536 with a PD-L1 inhibitor led to more potent antitumor activity in an MSLN expressing ovarian cancer xenograft model. Similar enhanced anti-tumor effects were shown in an MSLN expressing lung cancer model for HPN536 in combination with anti-PD1 or an anti-PD1 antibody. These data demonstrate the potential utility of PD1/PD-L1 blockade to enhance the potency of TriTAC mediated tumor cell killing.

"These data from Harpoon’s poster presentations at AACR (Free AACR Whitepaper) underscore the potential for further investigations of additional tumor targets, combination approaches with TriTACs, and conditionally active T cell engager prodrugs, or ProTriTACs, which may lead to greater tumor specificity, enhanced efficacy, and improved tolerability for patients," said Holger Wesche, Ph.D., chief scientific officer of Harpoon Therapeutics. "I am encouraged by these findings and look forward to future validation in the clinic."