An Exploratory Phase 1/2 Trial to Determine Recommended Phase 2 Dose (RP2D), Safety and Preliminary Efficacy of bb2121 (Ide-cel) Combinations in Subjects With Relapsed/Refractory Multiple Myeloma (KarMMa-7)

This is a global, open-label, multi-arm, multi-cohort, multi-center, phase 1/2 study to determine the safety, tolerability, efficacy, PK of bb2121 in combination with other therapies in adult subjects with R/RMM.
The following combinations will be
Arm A will test bb2121 in combination with CC-220 (± low-dose dexamethasone)
Arm B will test bb2121 in combination with BMS-986405 (JSMD194)
Combination agents being tested may be administered before, concurrently with and/or following (ie, maintenance) bb2121 infusion.
The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

Start Date01 Jun 2021

Sponsor / Collaborator

Celgene Corp.

NCT04036461 / TerminatedPhase 1

A Phase 1, Multicenter, Open-label, Dose Finding Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Subjects With Relapsed and Refractory Multiple Myeloma

Study CC-99712-MM-001 is an open-label, Phase 1, dose escalation (Part A) and expansion (Part B), First-in-Human (FIH) clinical study of CC-99712 in monotherapy or combination with BMS-986405 in participants with relapsed and refractory multiple myeloma (MM). The dose escalation part (Part A) of the study will evaluate the safety and tolerability of escalating doses of CC-99712, administered intravenously (IV) in monotherapy (Arm 1) or combination with BMS-986405 (Arm 2), to determine the maximum tolerated dose (MTD) of CC-99712 guided by a Bayesian logistic regression model (BLRM). A modified accelerated titration design will also be used for Arm 1 and Arm 2. The MTD may be established separately for CC-99712 administered at Q3W and/ or Q4W schedules. The expansion part (Part B) will further evaluate the safety and efficacy of CC-99712 in monotherapy (Arm 1) or combination (Arm 2) administered at or below the MTD in selected expansion cohorts in order to determine the RP2D. One or more doses or dosing regimens may be selected for cohort expansion. All participants will be treated until confirmed disease progression per IMWG criteria, unacceptable toxicity, or participants//Investigator decision to withdraw.

Start Date26 Aug 2019

Sponsor / Collaborator

Celgene Corp.

NCT03502577 / TerminatedPhase 1IIT

A Phase I Study of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells in Combination With JSMD194, a Small Molecule Inhibitor of Gamma Secretase, in Patients With Relapsed or Persistent Multiple Myeloma

This phase I trial determines the side effects and best dose of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T-cells when combined with gamma-secretase inhibitor LY3039478 (JSMD194), cyclophosphamide, and fludarabine in treating participants with multiple myeloma that that has come back or remains despite treatment. Placing genes added in the laboratory into immune T-cells may make the T-cells recognize BCMA, a protein on the surface of cancer cells. JSMD194 may enhance the killing of cancer cells by increasing the BCMA expression on multiple myeloma cells, making the targeted BCMA CAR-T treatment more effective. JSMD194 also decreases the amount of BCMA found in the circulation (called soluble BCMA) that is not bound to the myeloma cells. JSMD194 can therefore reduce the potential for soluble BCMA to act as a decoy. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BCMA CAR T therapy with JSMD194, cyclophosphamide, and fludarabine may work better in treating participants with relapsed or persistent multiple myeloma.

Start Date23 May 2018

Sponsor / Collaborator

Fred Hutchinson Cancer Research Center

[+2]

100 Clinical Results associated with Crenigacestat

100 Translational Medicine associated with Crenigacestat

100 Patents (Medical) associated with Crenigacestat

Literatures (Medical) associated with Crenigacestat

20 Oct 2024·Zhongguo fei ai za zhi = Chinese journal of lung cancer

[GINS1 Enhances Glycolysis, Proliferation and Metastasis in Lung Adenocarcinoma Cells by Activating the Notch/PI3K/AKT/mTORC1 Signaling Pathway].

Article

Author: Huo, Yishan ; Ma, Xiumin ; Xu, Xiaohui ; Feng, Yangchun

BACKGROUND:

Lung cancer is the most common type of cancer, accounting for more than half of all cancer cases, with lung adenocarcinoma (LUAD) representing over half of lung cancer patients. Currently, the 5-year survival rate for metastatic LUAD patients remains low and there is an urgent need for new biomarkers as targets for targeted therapy. Go-Ichi-Ni-San 1 (GINS1), an important member of the GINS family, is closely related to the occurrence and development of human malignant tumors. This study aims to explore the role of GINS1 in glycolysis, proliferation, and metastasis of LUAD cells and the related molecular mechanisms.

METHODS:

The expression of GINS1 was analysed using bioinformatics between LUAD patients and healthy controls. The expression levels of GINS1 in LUAD and adjacent tissues were detected by immunohistochemistry and Western blot. Western blot and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) were used to detect the expression of GINS1 in LUAD cell lines A549, SK-LU-1, Calu-3, H1299 and BEAS-2B. Stably knockdown GINS1 in A549 cells and its negative control cell line, as well as stably overexpress GINS1 in H1299 cells and its negative control cell line, were constructed by lentiviral transduction. Colony formation test was used to detect cell proliferation. Scratch test was used to detect cell migration. Transwell test was used to detect cell invasion, and the test kits were used to detect glucose consumption and lactate production. The expression levels of glycolysis-related proteins, Notch signaling pathway proteins and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway proteins were detected by Western blot. The Notch receptor agonist Jagged1 was added to cells from the shGINS1-A549 group and the Notch receptor inhibitor LY3039478 was added to cells from the GINS1-OE-H1299 group for the regression assay.

RESULTS:

The expression of GINS1 was up-regulated in LUAD patients, tissues and cell lines, and correlated with overall survival (P<0.05). Knockdown of GINS1 significantly inhibited the proliferation, migration and invasion of A549 cells (P<0.05), while overexpression of GINS1 significantly enhanced the proliferation, migration and invasion of H1299 cells (P<0.05). Furthermore, knockdown of GINS1 resulted in reduced glucose consumption, reduced lactate production, and reduced expression levels of glycolytic-related proteins in A549 cells (P<0.05); overexpression of GINS1 enhanced glycolytic level in H1299 cells (P<0.05). The expression levels of Notch1, Notch3, phosphorylated-PI3K (p-PI3K), phosphorylated-AKT (p-AKT) and phosphorylated-mTORC1 (Ser2448)[p-mTORC1 (Ser2448)] in A549 cells were significantly decreased by GINS1 knockdown (P<0.05), while the expression levels of PI3K, AKT, mTOR and p-mTORC2 (Ser2481) were not significantly changed (P>0.05). Overexpression of GINS1 increased the levels of Notch1, Notch3 and PI3K/AKT/mTORC1 pathway phosphorylated proteins in H1299 cells (P<0.05). Jagged1 significantly reversed the inhibition of glycolysis, proliferation and metastasis induced by GINS1 knockdown in A549 cells (P<0.05), and LY3039478 significantly inhibited the enhancement of glycolysis, proliferation and metastasis induced by GINS1 overexpression in H1299 cells (P<0.05).

CONCLUSIONS:

The expression of GINS1 enhances the expression of Notch1 and Notch3 receptors, and then phosphorylates and activates the downstream PI3K/AKT/mTORC1 signaling pathway to enhance the glycolysis, proliferation and metastasis of LUAD cells.

01 Dec 2023·Journal of hepatology

Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma

Article

Author: Wang, Tao ; Qiu, Yuan ; Jiang, Chenhao ; Ye, Linsen ; Xiang, Andy Peng ; Wang, Jinkai ; Liu, Yasong ; Lv, Guo ; Yao, Jia ; Lu, Tongyu ; Zheng, Jun ; He, Xinyi ; Ren, Zhijun ; Yang, Yang ; Li, Hua ; Wang, Jiancheng ; Li, Weiqiang ; Wang, Hongmiao ; Chen, Haitian ; Wang, Yi ; Cai, Jianye ; Sui, Xin ; Zhang, Yingcai ; Huang, Jianyang ; Kang, Yinqian ; Guan, Yuanjun ; Lai, Xiaofan ; Sun, Xiang ; Chen, Guihua ; Chen, Huaxin

BACKGROUND & AIMS:

Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression.

METHODS:

In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used a 3D invasion assay and in vivo bioluminescence imaging. We used periostin-knockout transgenic mice to uncover the role of the tumor microenvironment on CD51 cleavage. Moreover, we used several clinically relevant HCC models, including patient-derived organoids and patient-derived xenografts, to evaluate the therapeutic efficacy of cilengitide in combination with the γ-secretase inhibitor LY3039478.

RESULTS:

We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation-related genes. Furthermore, we identified cancer-associated fibroblast-derived periostin as the major driver of CD51 cleavage. Lastly, we showed that cilengitide-based therapy led to a dramatic therapeutic effect when supplemented with LY3039478 in both patient-derived organoid and xenograft models.

CONCLUSIONS:

In summary, we revealed previously unrecognized mechanisms by which CD51 is involved in HCC progression and uncovered the underlying cause of cilengitide treatment failure, as well as providing evidence supporting the translational prospects of combined CD51-targeted therapy in the clinic.

IMPACT AND IMPLICATIONS:

Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, failed in a phase III clinical trial. This prompted further investigation into the underlying mechanisms of CD51's effects. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51.

01 Oct 2023·Biochimica et biophysica acta. Molecular basis of disease

Hepatocyte CD36 protects mice from NASH diet-induced liver injury and fibrosis via blocking N1ICD production

Article

Author: Li, Yanping ; Ruan, Xiongzhong ; Zhao, Lei ; Zhao, Zhibo ; Li, Yuqi ; Zhang, Linkun ; Ding, Qiuying ; Luo, Jinfeng ; Chen, Yaxi ; Jiao, Junkui

BACKGROUND & AIMS:

Fatty acid translocase CD36 (CD36/FAT) is a widely expressed membrane protein with multiple immuno-metabolic functions. Genetic CD36 deficiency is associated with increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients. Liver fibrosis severity mainly affects the prognosis in patients with MAFLD, but the role of hepatocyte CD36 in liver fibrosis of MAFLD remains unclear.

METHODS:

A high-fat high-cholesterol diet and a high-fat diet with high-fructose drinking water were used to induce nonalcoholic steatohepatitis (NASH) in hepatocyte-specific CD36 knockout (CD36LKO) and CD36flox/flox (LWT) mice. Human hepG2 cell line was used to investigate the role of CD36 in regulating Notch pathway in vitro.

RESULTS:

Compared to LWT mice, CD36LKO mice were susceptible to NASH diet-induced liver injury and fibrosis. The analysis of RNA-sequencing data revealed that Notch pathway was activated in CD36LKO mice. LY3039478, an inhibitor of γ-secretase, inhibited Notch1 protein S3 cleavage and Notch1 intracellular domain (N1ICD) production, alleviating liver injury and fibrosis in CD36LKO mice livers. Likewise, both LY3039478 and knockdown of Notch1 inhibited the CD36KO-induced increase of N1ICD production, causing the decrease of fibrogenic markers in CD36KO HepG2 cells. Mechanistically, CD36 formed a complex with Notch1 and γ-secretase in lipid rafts, and hence CD36 anchored Notch1 in lipid rafts domains and blocked Notch1/γ-secretase interaction, inhibiting γ-secretase-mediated cleavage of Notch1 and the production of N1ICD.

CONCLUSIONS:

Hepatocyte CD36 plays a key role in protecting mice from diet-induced liver injury and fibrosis, which may provide a potential therapeutic strategy for preventing liver fibrogenesis in MAFLD.

News (Medical) associated with Crenigacestat

11 May 2023

·www.globenewswire.com

Harpoon Therapeutics Reports First Quarter 2023 Financial Results and Provides Corporate Update

Enrollment for HPN217 (BCMA) and HPN328 (DLL3) remain on track, with data updates and selection of recommended Phase 2 doses for both ongoing clinical programs planned in 2023 Five preclinical posters presented at AACR 2023 in April on HPN217, HPN328 and ProTriTAC™ development candidates Following $25 million financing in March, cash and equivalents of $61.4 million expected to fund current operations into second half of 2024 SOUTH SAN FRANCISCO, Calif., May 11, 2023 (GLOBE NEWSWIRE) -- Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immuno-oncology company developing novel T cell engagers, today reported financial results for the first quarter ended March 31, 2023 and provided a corporate update. “Harpoon is executing its business plan in 2023 with a strengthened balance sheet, advancing multiple programs based on the TriTAC® platform, and ProTriTAC™ IND candidates ready for further development,” said Julie Eastland, President and Chief Executive Officer of Harpoon Therapeutics. “Following the $25 million preferred equity financing in March 2023, we have the financial strength to fund current operations into the second half of 2024. Additionally, we expect to see a positive impact on our cash burn over the course of the year from the restructuring implemented in the fourth quarter of last year. We also anticipate completion of enrollment for two of our Phase 1 clinical programs, HPN217 and HPN328, and achievement of key data milestones this year. Our clinical and leadership teams remain focused on advancing a rich pipeline of next-generation T cell engagers to address a broad patient population with unmet needs in both solid tumor and blood cancer indications.” Corporate Update / Recent and Upcoming Highlights Tri-specific T cell Activating Construct (TriTAC®) PlatformHPN217 (BCMA) Phase 1 trial for relapsed, refractory multiple myeloma Interim results reported at the 64th American Society of Hematology (ASH) Annual Meeting (cut-off of October 17, 2022) demonstrated continued evidence of clinical activity with 77% (10/13) ORR observed in the two highest target dose levels (12 and 24 mg).Overall low incidence of cytokine release syndrome (CRS) across the patient population studied to date.Completion of Phase 1 dose exploration is expected in the first half of 2023, with identification of a recommended Phase 2 dose(s) expected by the end of 2023.Data presentation anticipated in the second half of 2023. HPN328 (DLL3) Phase 1/2 trial in small cell lung cancer (SCLC) and neuroendocrine cancers Observations in the monotherapy cohorts, as of February 2023, included early signs of anti-tumor activity, with two confirmed partial responses per RECIST in patients with SCLC.Phase 1/2 dose and schedule optimization trial ongoing with monotherapy cohorts enrolling at the 24 mg target dose.Enrollment in combination therapy of HPN328 with atezolizumab (Tecentriq®) in patients with SCLC, as part of the Phase 1/2 dose escalation trial, is anticipated to begin in the second half of 2023.Phase 1 dose exploration is expected to complete in the second half of 2023, including the identification of a recommended Phase 2 dose(s) in the monotherapy setting by the end of 2023.Data presentation anticipated in the second half of 2023. ProTriTAC™ HPN601 (EpCAM) HPN601 is Harpoon’s first conditionally active T cell engager based on the ProTriTAC™ platform. EpCAM is expressed in a broad range of solid tumors, potentially enabling HPN601 to address multiple indications with high unmet medical need.IND filing timeline to enable a Phase 1 dose exploration study dependent on resource allocation. Two additional candidates Two new candidates for potential IND-enabling studies from the ProTriTAC platform have been identified against the targets trophoblast cell surface antigen 2 (TROP2) and Integrin-β6 (ITGB6). TriTAC-XR® The proprietary TriTAC-XR extended-release T cell engager platform is designed to minimize on-target CRS, a characteristic of many T cell engagers that can lead to dose limiting toxicities and can reduce the efficacy of these potent anti-tumor drugs. AACR 2023 – Five Preclinical Posters Presented HPN217: Poster presented on April 18, 2023: “Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models” In preclinical mouse models, γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines.Combination therapy with 1mg/kg LY-3039478 and a subtherapeutic dose of 4ug/kg HPN217 led to decreased tumor burden and increased survival in a disseminated MOLP8 xenograft compared to either monotherapy alone. HPN328: Two posters presented on April 18, 2023: “Long-term anti-tumor immunity induced by HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, in a preclinical immunocompetent mouse model” These results suggest that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, with an increase in memory T cells, suggesting a novel mechanism for its activity and efficacy in vivo. These findings suggest that long-term anti-tumor immunity induced by HPN328 can potentially lead to more durable anti-tumor responses in cancer patients “Anti-tumor activity of HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, is enhanced by combining with an anti-PD-L1 antibody in an immunocompetent mouse model” These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combination approach in patients.Clinical studies of HPN328 in combination with atezolizumab are planned. ProTriTAC™: Two posters presented on April 17, 2023 introducing new candidates for IND-enabling studies: “TROP2 ProTriTAC™, a protease-activated T cell engager prodrug targeting TROP2 for the treatment of solid tumors”“ITGB6 ProTriTAC™, a protease-activated T cell engager prodrug targeting Integrin-β6 for the treatment of solid tumors”Both data sets support further investigation of Harpoon’s conditionally active next-generation T cell engager platform, ProTriTAC™, with demonstrated therapeutic potential in a broad range of TROP2- and ITGB6-expressing solid tumors. Corporate Update $25 million preferred equity financing closed in March 2023, extending cash runway into the second half of 2024. First Quarter 2023 Financial Results Harpoon ended the first quarter of 2023 with $61.4 million in cash and cash equivalents compared to $53.1 million as of December 31, 2022. Following the $25.0 million preferred equity financing and year to date ATM sales, cash and cash equivalents are expected to fund current operations into the second half of 2024. Revenue for the quarter ended March 31, 2023 was $8.6 million, compared to $5.9 million for the first quarter ended March 31, 2022. The increase in revenue was primarily due to revenue recognized in first quarter 2023 for research and development services performed on the fourth target under Harpoon’s Restated Collaboration Agreement with AbbVie, and an increase in revenue recognized related to Harpoon’s Development and Option Agreement with AbbVie for research and development services performed.Research and development (R&D) expense for the quarter ended March 31, 2023 was $15.2 million, reduced from $20.8 million during the first quarter ended March 31, 2022. The decrease primarily arose from lower personnel-related costs due to corporate restructuring implemented in November 2022 and lower clinical and development costs due to the wind down of the HPN424 and HPN536 programs.General and administrative (G&A) expense for the quarter ended March 31, 2023 decreased to $4.2 million, compared to $5.4 million for the first quarter ended March 31, 2022. The decrease was primarily attributable to lower personnel-related expenses, lower legal costs, and lower professional service fees to support Harpoon’s operations. Net loss for the first quarter ended March 31, 2023 was $11.3 million, improved from $20.3 million for the first quarter ended March 31, 2022. About Harpoon Therapeutics Harpoon Therapeutics is a clinical-stage immuno-oncology company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patient’s own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. Harpoon has also developed a proprietary ProTriTAC™ platform, which applies a prodrug concept to its TriTAC platform to create a therapeutic T cell engager that remains inactive until it reaches the tumor. Harpoon’s third proprietary technology platform, extended release TriTAC-XR, is designed to mitigate cytokine release syndrome. For additional information about Harpoon Therapeutics, please visit www.harpoontx.com. Cautionary Note on Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipate,” “may,” “expect,” “plan,” “potential,” “further,” “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Harpoon Therapeutics’ expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Harpoon Therapeutics’ clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the expected progress, results, and plans pertaining to Harpoon Therapeutics’ clinical trials, including timing, scope, design and interim results of clinical trials and the safety and tolerability profile of product candidates, the association of interim clinical data and preclinical results with potential treatment outcomes, achievement of future milestones, cash sufficiency forecasts, including ability to extend cash runway as a result of the restructuring and financing activities, and other statements that are not historical fact. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during clinical studies, preliminary data and trends may not be predictive of future data or results, may not demonstrate safety or efficacy or lead to regulatory approval by the FDA or other regulatory agencies, clinical trial site activation or enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, the uncertainties and timing of the regulatory approval process, the timing and results of unexpected litigation or other disputes, and the sufficiency of Harpoon Therapeutics’ cash resources, including that Harpoon Therapeutics may not achieve the expected benefits of its restructuring or may incur unexpected additional expenses in connection with such restructuring. These and other factors that may cause Harpoon Therapeutics’ actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Harpoon Therapeutics’ filings with the U.S. Securities and Exchange Commission, including under “Risk Factors” in Harpoon Therapeutics’ quarterly report on Form 10-Q for the quarter ended March 31, 2023, and future filings by Harpoon Therapeutics. Except as required by law, Harpoon Therapeutics assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contacts: Investors:ICR WestwickeRobert H. Uhl619-228-5886 robert.uhl@westwicke.com Media:uncapped Communications303-588-0599kerry.walton@uncappedcommunications.com Harpoon Therapeutics, Inc.Statement of Operations and Comprehensive Loss(Unaudited) (in thousands, except share and per share amounts) For the Three Months Ended March 31, 2023 2022 Revenue Collaboration and license revenue $8,583 $5,906 Total revenue 8,583 5,906 Operating expenses Research and development 15,163 20,818 General and administrative 4,185 5,401 Total operating expenses 19,348 26,219 Loss from operations (10,765) (20,313)Interest income, net 425 40 Interest expense (138) — Other expense, net (860) (48)Net loss attributable to common stockholders (11,338) (20,321)Other comprehensive loss: Net unrealized loss on marketable securities 3 (41)Comprehensive loss $(11,335) $(20,362)Net loss attributable to common stockholders per share, basic and diluted (0.31) (0.62)Weighted-average shares used in computing net loss per share, basic and diluted 36,968,214 32,879,188 Harpoon Therapeutics, Inc.Selected Balance Sheet Data(Unaudited) March 31,2023 December 31,2022 (in thousands) Cash and cash equivalents $61,385 $53,112 Total assets $80,809 $73,729 Total liabilities $80,094 $68,330 Total stockholders' equity $715 $5,399

Phase 1AACRFinancial StatementASHClinical Result

20 Apr 2023

·pipelinereview.com

Harpoon Therapeutics Presents Preclinical Results for Novel T Cell Engagers HPN217 and HPN328 at AACR 2023

SOUTH SAN FRANCISCO, CA, USA I April 18, 2023 I Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immuno-oncology company developing novel T cell engagers, today presented preclinical data for two of its key clinical programs, HPN328 and HPN217, in three poster presentations at the American Association for Cancer Research (AACR) Annual Meeting being held in Orlando, Fla., April 14-19, 2023. HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC ® ) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is Harpoon’s half-life extended TriTAC that targets delta-like canonical Notch ligand 3 (DLL3). “These data provide further validation of our proprietary TriTAC T cell engager platform, indicating potential for long-term immunity induced by HPN328, as well as clinical effect in combination with anti-PD-L1 antibodies,” said Banmeet Anand, Ph.D., Senior Vice President, Translational Medicine, Harpoon Therapeutics. “Results also support our continued clinical development efforts for HPN217, with encouraging preclinical results in combination with γ-secretase inhibitors (GSIs).” “With our Phase 1 trial ongoing and further studies planned, we look forward to continuing our clinical development efforts for these two promising programs,” added Luke Walker, M.D., Chief Medical Officer of Harpoon Therapeutics. Highlights from the posters include: Abstract #4131: Long-term anti-tumor immunity induced by HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, in a preclinical immunocompetent mouse model In an immunocompetent MC38-hDLL3 murine cancer model, HPN328 showed dose dependent anti-tumor activity and increased CD8+ tumor infiltrated lymphocyte (TIL) activation which was maintained upon reintroduction of a second tumor on the opposite flank, and discontinuing treatment. These results suggested that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, with an increase in memory T cells, suggesting a novel mechanism for its activity and efficacy in vivo. Overall, these findings indicate that long-term anti-tumor immunity induced by HPN328 can potentially lead to more durable anti-tumor responses in cancer patients. Abstract #5070: Anti-tumor activity of HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, is enhanced by combining with an anti-PD-L1 antibody in an immunocompetent mouse model In an immunocompetent mouse model, sub-therapeutic doses of HPN328 in combination with an anti-PD-L1 antibody demonstrated enhanced, dose dependent anti-tumor activity when compared to either treatment alone and showed increased activation in memory CD8+ T cells. These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combination approach in patients. Clinical studies of HPN328 in combination with atezolizumab are planned. Abstract #5081: Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ -secretase inhibitors in preclinical models γ-secretase inhibitors (GSIs) have been shown to increase membrane bound BCMA expression on multiple myeloma cells, providing a rationale for studying this combination approach. In preclinical mouse models, γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines. Specifically, combination therapy with 1mg/kg LY-3039478 and a subtherapeutic dose of 4ug/kg HPN217 led to decreased tumor burden and increased survival in a disseminated MOLP8 xenograft compared to either monotherapy alone. For more details about the AACR Annual Meeting, please visit: https://www-aacr-org.libproxy1.nus.edu.sg/meeting/aacr-annual-meeting-2023/ The posters will be available on Harpoon’s website following today’s presentations. About HPN217 HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC ® ) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN217 is being evaluated in an ongoing Phase 1, multicenter, open-label dose escalation study designed to evaluate safety, tolerability, pharmacokinetics (PK) and clinical activity in patients with relapsed/refractory multiple myeloma who have had at least three prior systemic treatments. In November 2019, Harpoon Therapeutics and AbbVie announced a licensing agreement and option to advance HPN217 and expand an existing discovery collaboration. Under the terms of the agreement, AbbVie may exercise its option to license HPN217 after completion of the Phase 1 clinical trial. In March 2022, the FDA granted Fast Track designation to HPN217, underscoring its potential to address a serious unmet medical need for patients with relapsed, refractory multiple myeloma. About HPN328 HPN328 targets delta-like canonical Notch ligand 3 (DLL3) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC ® ) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is being evaluated as monotherapy in an ongoing open-label, multicenter two-part study to assess the safety, tolerability and pharmacokinetics in patients with advanced cancers associated with expression of DLL3. In March 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to HPN328 for the treatment of small cell lung cancer (SCLC). About Harpoon Therapeutics Harpoon Therapeutics is a clinical-stage immuno-oncology company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patient’s own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC ® ) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. Harpoon has also developed a proprietary ProTriTAC™ platform, which applies a prodrug concept to its TriTAC platform to create a therapeutic T cell engager that remains inactive until it reaches the tumor. Harpoon’s third proprietary technology platform, extended release TriTAC-XR, is designed to mitigate cytokine release syndrome. For additional information about Harpoon Therapeutics, please visit www.harpoontx.com . SOURCE: Harpoon Therapeutics

License out/inPhase 1ImmunotherapyOrphan DrugFast Track

19 Apr 2023

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Harpoon Therapeutics Presents Preclinical Results for Novel T Cell Engagers HPN217 and HPN328 at AACR 2023

Preclinical results for HPN328 suggest potential for long-term anti-tumor immunity and durable responses in patients, as well as utility of combining anti-PD-L1 antibodies to enhance anti-tumor activity γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines, supporting further study of combination approach SOUTH SAN FRANCISCO, Calif., April 18, 2023 (GLOBE NEWSWIRE) -- Harpoon Therapeutics, Inc, (Nasdaq: HARP), a clinical-stage immuno-oncology company developing novel T cell engagers, today presented preclinical data for two of its key clinical programs, HPN328 and HPN217, in three poster presentations at the American Association for Cancer Research (AACR) Annual Meeting being held in Orlando, Fla., April 14-19, 2023. HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC®) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is Harpoon’s half-life extended TriTAC that targets delta-like canonical Notch ligand 3 (DLL3). “These data provide further validation of our proprietary TriTAC T cell engager platform, indicating potential for long-term immunity induced by HPN328, as well as clinical effect in combination with anti-PD-L1 antibodies,” said Banmeet Anand, Ph.D., Senior Vice President, Translational Medicine, Harpoon Therapeutics. “Results also support our continued clinical development efforts for HPN217, with encouraging preclinical results in combination with γ-secretase inhibitors (GSIs).” “With our Phase 1 trial ongoing and further studies planned, we look forward to continuing our clinical development efforts for these two promising programs,” added Luke Walker, M.D., Chief Medical Officer of Harpoon Therapeutics. Highlights from the posters include: Abstract #4131: Long-term anti-tumor immunity induced by HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, in a preclinical immunocompetent mouse model In an immunocompetent MC38-hDLL3 murine cancer model, HPN328 showed dose dependent anti-tumor activity and increased CD8+ tumor infiltrated lymphocyte (TIL) activation which was maintained upon reintroduction of a second tumor on the opposite flank, and discontinuing treatment. These results suggested that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, with an increase in memory T cells, suggesting a novel mechanism for its activity and efficacy in vivo. Overall, these findings indicate that long-term anti-tumor immunity induced by HPN328 can potentially lead to more durable anti-tumor responses in cancer patients. Abstract #5070: Anti-tumor activity of HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, is enhanced by combining with an anti-PD-L1 antibody in an immunocompetent mouse model In an immunocompetent mouse model, sub-therapeutic doses of HPN328 in combination with an anti-PD-L1 antibody demonstrated enhanced, dose dependent anti-tumor activity when compared to either treatment alone and showed increased activation in memory CD8+ T cells. These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combination approach in patients. Clinical studies of HPN328 in combination with atezolizumab are planned. Abstract #5081: Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models γ-secretase inhibitors (GSIs) have been shown to increase membrane bound BCMA expression on multiple myeloma cells, providing a rationale for studying this combination approach. In preclinical mouse models, γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines. Specifically, combination therapy with 1mg/kg LY-3039478 and a subtherapeutic dose of 4ug/kg HPN217 led to decreased tumor burden and increased survival in a disseminated MOLP8 xenograft compared to either monotherapy alone. For more details about the AACR Annual Meeting, please visit: The posters will be available on Harpoon’s website following today’s presentations. About HPN217 HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC®) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN217 is being evaluated in an ongoing Phase 1, multicenter, open-label dose escalation study designed to evaluate safety, tolerability, pharmacokinetics (PK) and clinical activity in patients with relapsed/refractory multiple myeloma who have had at least three prior systemic treatments. In November 2019, Harpoon Therapeutics and AbbVie announced a licensing agreement and option to advance HPN217 and expand an existing discovery collaboration. Under the terms of the agreement, AbbVie may exercise its option to license HPN217 after completion of the Phase 1 clinical trial. In March 2022, the FDA granted Fast Track designation to HPN217, underscoring its potential to address a serious unmet medical need for patients with relapsed, refractory multiple myeloma. About HPN328 HPN328 targets delta-like canonical Notch ligand 3 (DLL3) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC®) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is being evaluated as monotherapy in an ongoing open-label, multicenter two-part study to assess the safety, tolerability and pharmacokinetics in patients with advanced cancers associated with expression of DLL3. In March 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to HPN328 for the treatment of small cell lung cancer (SCLC). About Harpoon Therapeutics Harpoon Therapeutics is a clinical-stage immuno-oncology company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients suffering from cancer and other diseases. T cell engagers are engineered proteins that direct a patient’s own T cells to kill target cells that express specific proteins, or antigens, carried by the target cells. Using its proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, Harpoon is developing a pipeline of novel TriTACs initially focused on the treatment of solid tumors and hematologic malignancies. Harpoon has also developed a proprietary ProTriTAC™ platform, which applies a prodrug concept to its TriTAC platform to create a therapeutic T cell engager that remains inactive until it reaches the tumor. Harpoon’s third proprietary technology platform, extended release TriTAC-XR, is designed to mitigate cytokine release syndrome. For additional information about Harpoon Therapeutics, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “look forward,” “may,” “suggest,” “plan,” “potential,” “continued,” “further,” “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Harpoon Therapeutics’ expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause Harpoon Therapeutics’ clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements about the expected progress, results, and plans pertaining to Harpoon Therapeutics’ clinical trials, the association of interim clinical data and preclinical results with potential treatment outcomes, the possibility and timing of AbbVie’s option to license HPN217 and other statements that are not historical fact. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during clinical studies, preliminary data and trends may not be predictive of future data or results, may not demonstrate safety or efficacy or lead to regulatory approval by the FDA or other regulatory agencies, clinical trial site activation or enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, the uncertainties and timing of the regulatory approval process, the timing and results of unexpected litigation or other disputes, and the sufficiency of Harpoon Therapeutics’ cash resources. These and other factors that may cause Harpoon Therapeutics’ actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Harpoon Therapeutics’ filings with the U.S. Securities and Exchange Commission, including under “Risk Factors” in Harpoon Therapeutics’ annual report on Form 10-K for the year ended December 31, 2022, and future filings by Harpoon Therapeutics. Except as required by law, Harpoon Therapeutics assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contacts: Investors: ICR Westwicke Robert H. Uhl Managing Director 858-356-5932 robert.uhl@westwicke.com Media: Uncapped Communications 303-588-0599 kerry.walton@uncappedcommunications.com

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Indication	Highest Phase	Country/Location	Organization	Date
Large Granular Lymphocytic Leukemia	Phase 2	US	Eli Lilly & Co.	01 Oct 2015
Large Granular Lymphocytic Leukemia	Phase 2	FR	Eli Lilly & Co.	01 Oct 2015
Large Granular Lymphocytic Leukemia	Phase 2	DE	Eli Lilly & Co.	01 Oct 2015
Large Granular Lymphocytic Leukemia	Phase 2	IL	Eli Lilly & Co.	01 Oct 2015
Large Granular Lymphocytic Leukemia	Phase 2	IT	Eli Lilly & Co.	01 Oct 2015
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	Phase 2	US	Eli Lilly & Co.	01 Oct 2015
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	Phase 2	FR	Eli Lilly & Co.	01 Oct 2015
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	Phase 2	DE	Eli Lilly & Co.	01 Oct 2015
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	Phase 2	IL	Eli Lilly & Co.	01 Oct 2015
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	Phase 2	IT	Eli Lilly & Co.	01 Oct 2015

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02784795 (I6F-MC-JJCD, Pubmed) Manual	Phase 1	Solid tumor	31	cisplatin+Gemcitabine+Crenigacestat	nwbdoiilkf(puhzirulqw) = rofytfcbmm klhhevjlyi (tdkdqbyayx ) View more	Negative	28 Aug 2022
				carboplatin+Gemcitabine+Crenigacestat	nwbdoiilkf(puhzirulqw) = jyatxkhuws klhhevjlyi (tdkdqbyayx ) View more
NCT02836600 (Pubmed) Manual	Phase 1	Advanced Malignant Solid Neoplasm	11	Crenigacestat (25mg)	zslaiksquq(jbwczyauoi) = There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. llktvhfqnf (cbxovwutio ) View more	Negative	01 Apr 2021
				Crenigacestat (50mg)
NCT02784795 (I6F-MC-JJCD, Pubmed \| Invest New Drugs)	Phase 1	Metastatic Solid Tumor	63	Crenigacestat + Taladegib	psniwpeyor(twbmftqoff) = txdxieyitq tshtkurcdr (tnafjjkmbx )	Negative	08 Mar 2021
				Crenigacestat + LY3023414	psniwpeyor(twbmftqoff) = fdtfrrgthl tshtkurcdr (tnafjjkmbx ) View more
NCT02518113 (JJCB, Pubmed \| Cancer) Manual	Phase 1/2	Precursor T-Cell Lymphoblastic Leukemia-Lymphoma \| Lymphoma	36	dexamethasone+Crenigacestat	iwmnymczzq(dhlxcumbga) = 6 patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75-mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100-mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125-mg cohort (grade 3 diarrhea, nausea, and vomiting) azdcpfqusy (bngotjfwzt ) View more	Negative	01 Feb 2021
NCT01695005 (Pubmed \| Eur J Cancer Care (Engl))	Phase 1	Gastrointestinal Stromal Tumors \| Soft Tissue Sarcoma	237	LY3039478 50mg/75 mg	tsxkbujcok(fwurjjqitp) = ekiignbbmw agvnwgaafd (stsswzjbdd, 4.3 - non to evaluable [NE]) View more	Positive	01 Nov 2018
NCT01695005 (ASCO2017) Manual	Phase 1	Adenoid Cystic Carcinoma	22	Crenigacestat	gctjvlebsl(xriauyvyyx) = tsmqzptydx wlujxzleyx (qeqovsxary, 2.4 - NE) View more	Positive	05 Jun 2017
				Crenigacestat (second line)	gctjvlebsl(xriauyvyyx) = xyleesicpz wlujxzleyx (qeqovsxary, 4.0 - NE)

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