Harpoon Therapeutics : Clin Cancer Res 2021; OnlineFirst version Jan 6, 2021 – Marketscreener.com
Posted: January 9, 2021 at 3:05 am
Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392
CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY
Preclinical Characterization of HPN536, a Trispecic, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors A C
Mary Ellen Molloy1, Richard J. Austin1, Bryan D. Lemon1, Wade H. Aaron1, Vaishnavi Ganti1, Adrie Jones1,
Susan D. Jones1, Kathryn L. Strobel1, Purbasa Patnaik1, Kenneth Sexton1, Laurie Tatalick1, Timothy Z. Yu1, Patrick A. Baeuerle1,2,3, Che-Leung Law1, and Holger Wesche1
ABSTRACT
Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol- linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast can- cer. Early signs of clinical efcacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic inter- vention, but therapies with improved efcacy are still needed to address the signicant unmet medical need posed by MSLN- expressing cancers.
Experimental Design: We designed HPN536, a 53-kDa, tri- specic, T-cell-activatingprotein-based construct, which binds to MSLN-expressing tumor cells, CD3e on T cells, and to serum albumin. Experiments were conducted to assess the potency, activ-
Introduction
Redirection of cytotoxic T cells with bispecic antibody constructs for cancer therapy has been validated in the clinic (1-6). Blinatumo- mab is the rst and thus far the only bispecic T-cell engager (BiTE) approved by the FDA (7). T-cell-engaging biologics function by forming an immunologic cytolytic synapse between cancer target cells and T cells, which leads to target cell lysis independent of T-cell receptor (TCR) specicity, peptide antigen presentation by HLA, and T-cell costimulation. Despite the clinical success of blinatumomab for treating relapsed and refractory acute lymphoblastic leukemia, other molecules, including BiTE antibodies, showed only limited activity in the treatment of solid tumors (8, 9). Their short plasma half-life required continuous intravenous infusion limiting their utility for most solid tumor indications. Novel designs for T-cell-engaging antibodies aim at overcoming limitations of the rst generation and are already being tested in clinical trials (10).
The Trispecic T-cell-Activating Construct (TriTAC) design has been specically developed to treat solid tumors (11). TriTACs consist of a single polypeptide chain aligning three humanized, antibody- derived binding domains: a single-domain antibody (sdAb) specic for
1Harpoon Therapeutics, South San Francisco, California. 2MPM Capital, Cam- bridge, Massachusetts. 3Institute for Immunology, Ludwig-Maximilians University Munich, Planegg- Martinsried, Munich, Germany.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: Mary Ellen Molloy, Harpoon Therapeutics, 131 Oyster
Point Boulevard, 300, South San Francisco, CA 94080. Phone: 773-318-0796;
E-mail: mmolloy@harpoontx.com
Clin Cancer Res 2020;XX:XX-XX
doi: 10.1158/1078-0432.CCR-20-3392
2020 American Association for Cancer Research.
ity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).
Results: HPN536 binds to MSLN-expressing tumor cells and to CD3e on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN- dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.
Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
a tumor antigen, a sdAb specic for serum albumin for half-life extension, and a single-chain fragment variable (scFv) specic for the CD3e subunit of the TCR complex (11). Their molecular size of 53 kDa is about one-third of that of an IgG. Binding of TriTACs to tumor antigen and CD3e is monovalent, which minimizes off-target CD3e clustering that can potentially lead to nonspecic T-cell activation. The absence of an Fc-gamma domain for half-life extension is functionally compensated by an albumin-binding domain. HPN424 (11) and HPN536, the rst two TriTACs are in phase I clinical testing in hormone refractory prostate cancer and mesothelin (MSLN)-over- expressing solid tumors, respectively.
Human MSLN is produced as a 71-kDa precursor of 628 amino acids, which is expressed as a glycophosphatidylinositol-linked cell surface glycoprotein. Its 31-kDaN-terminal domain is released as a soluble protein, termed as the megakaryocyte potentiating factor (MPF), while the 40-kDaC-terminal domain remains attached to the plasma membrane as mature MSLN (12-14). MSLN expression on normal tissue is conned to the single-cell mesothelial layer covering the surface of tissues and organs of the pleural, pericardial, and peritoneal cavities (13, 15). MUC16/CA125 is a binding partner for MSLN, implicating a role for MSLN in cell adhesion (16, 17). However, the precise physiologic functions of MSLN have not been dened, and MSLN-knockout mice exhibit no detectable phenotype or developmental abnormality (18).
MSLN is overexpressed in many malignancies, including ovarian cancer (13, 15, 19), pancreatic cancer (20, 21), non-small cell lung cancer (22-26),triple-negative breast cancer (26, 27), and mesothe- lioma (28, 29). In triple-negative breast cancer (25) and in lung and pancreatic adenocarcinomas (22, 23, 30), overexpression of MSLN correlates with poor prognosis. Differential expression of MSLN in cancer versus normal tissue has made it an attractive target for MSLN- directed imaging agents and therapeutics (10, 31-33). A challenge in developing MSLN-directed therapeutics is the expression of MSLN on normal mesothelial cells, potentially leading to dose-limiting toxicities.
Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392
Molloy et al.
Translational Relevance
Patients with mesothelin (MSLN)-overexpressing tumors, including ovarian, pancreatic, lung, and triple-negative breast cancer, have a high unmet clinical need. A number of MSLN- targeted therapeutics have been developed that show limited efcacy and safety in clinical trials. HPN536 is a novel, MSLN- targeted, trispecic, T-cell-activating protein construct that can potently redirect T cells to lyse tumor cells and was remarkably well tolerated in nonhuman primates at single doses up to 10 mg/kg, which is far above the expected therapeutic dose level. Our ndings suggest that HPN536 has the potential for high clinical activity and a wide therapeutic window. Its long serum half-life supports once-weekly dosing in humans. Currently, HPN536 is the only MSLN-targeting,T-cell-engaging biologic in clinical testing.
HPN536 specically redirects T cells for potent redirected lysis of MSLN-expressing cancer cells with concomitant T-cell activation. In three different mouse xenograft models, HPN536 induced durable antitumor activity at very low doses. In cynomolgus monkeys, HPN536 was well tolerated, showed a long serum half-life, and elicited signs of target engagement on mesothelial structures.
Materials and Methods
Protein production
Sequences of TriTACs, sdAbs, and extracellular domains of target proteins fused to an Fc domain or a hexahistidine tag were cloned into mammalian expression vector, pcDNA 3.4 (Invitrogen), preceded by a leader sequence. Expi293 Cells (Life Technologies) were maintained in suspension in Optimum Growth Flasks (Thomson) between 0.2 and
8 106 cells/mL in Expi293 media. Puried plasmid DNA was transfected into Expi293 cells in accordance with Expi293 Expression System Kit (Life Technologies) protocols and cultured for 4-6 days after transfection. Alternatively, HPN536 was produced in CHO- DG44 DHFR-decient cells (34). The amount of expressed proteins in conditioned media was quantitated using an Octet RED96 instru- ment with Protein A Tips (ForteBio/Pall) using appropriate puried control proteins for a standard curve. Conditioned media from either host cell were ltered and puried by protein A afnity and desalted or subjected to preparative size exclusion chromatography (SEC) using an AKTA Pure Chromatography System (GE Healthcare). Protein A puried TriTAC proteins were further puried by ion exchange and
formulated in a buffered solution containing excipients. Final purity was assessed by SDS-PAGE by resolving 2.5 mg/lane on TRIS-Glycine
gels and visualized with Simply Blue Stain (Life Technologies). Native purity was also assessed by analytic SEC using a Yarra SEC150 3 mm
4.6 150 mm Column (Phenomenex) resolved in an aqueous/organic mobile phase buffered at neutral pH on a 1290 LC system and peaks were integrated with OpenLab ChemStation Software (Agilent Technologies).
In vitro afnity measurements
Afnities of HPN536 analyte for albumin, CD3e, and MSLN ligands were measured by biolayer interferometry using an Octet RED96 instrument with Streptavidin Tips (ForteBio/Pall). Experiments were performed at 27 C in PBS plus casein in the absence or presence of 15 mg/mL has, as described in Results section and gure legends. Binding sensograms generated from empirically determined ligand
loads, appropriate serial dilutions of known analyte concentrations, and association and dissociation times were then t globally to a one- to-one binding model using Octet DataAnalysis 9.0 software.
In vitro T-cell-dependent cell cytotoxicity and T-cell activation assays
T cells from healthy donors were puried from leukopaks (leuka- pheresis samples, StemCell Technologies) using EasySep Human T Cell Isolation Kits (StemCell Technologies, 17951) following the manufacturer's instructions. All cancer cell lines were obtained from the ATCC, with the exception of OVCAR8 cells, which were obtained from the NCI (Bethesda, MD). Cell lines were passaged a maximum of 36 times after being received from the ATCC. Cell line authentication and Mycoplasma testing were not performed. T-cell-dependent cell cytotoxicity (TDCC) assays were performed as described previously (35). Briey, luciferase-expressing target cells and puried human T cells were seeded per well of a 384-well plate at a 10:1 T cell-to-target cell ratio. Target cell killing was assessed following incubation for 48 hours at 37oC and 5% CO2. Target cell viability was assessed by incubation with the SteadyGlo Reagent (Promega). Luminescence was measured using a PerkinElmer EnVision Detection System. Activated T cells were identied by CD69 and CD25 surface expression (BD Biosciences). Samples were analyzed on a FACSCelesta Flow Cyt- ometer (BD Biosciences). Flow cytometry data were processed using FlowJo v10 Software (FlowJo, LLC).
Binding of HPN536 on MSLN-expressing OVCAR and T cells Cultured cells were incubated with 1 mg/mL HPN536 or anti-GFP
TriTAC (control) for 1 hour. Binding was detected using Alexa647- anti-TriTAC antibody using a FACSCelesta Flow Cytometer (BD Biosciences). The QIFIKIT (Dako) was used according to the man- ufacturer's instructions to estimate the number of MSLN molecules expressed per cell.
Cytokines in the presence of T cells
To measure the cytokines, AlphaLISA Kits were used (PerkinElmer) per the manufacturer's instructions, except that the assays were performed in 384-well plates instead 96-well plates. Plates containing conditioned media from TDCC assays were used for analysis. Plates were read on a PerkinElmer EnVision Plate Reader equipped with an AlphaLISA module.
In vivo mouse efcacy studies
All mouse studies were performed in accordance with the policies of the Institutional Animal Care and Use Committee (IACUC) at
Harpoon Therapeutics and Charles River Laboratories. For TOV21G and HPAFII experiments, NCG (NOD-Prkdcem26Cd52Il2rgem26Cd22/
NjuCrl) mice received subcutaneous coimplants of human cancer cells (5 106) and human T cells (5 106) in 50% Matrigel (BD Biosciences) on day 0. Human T cells were expanded before implantation using Human T Cell Activation/Expansion Kit (Miltenyi Biotec) according to the manufacturer's instructions. Mice were dosed on days 1-15 (HPAFII, Fig. 4A and TOV21G, Fig. 4C) or days 7-16 (HPAFII, Fig. 4B) via intraperitoneal injection. For NCI-H292 experi- ments, NCG mice received subcutaneous coimplants of human cancer cells (1 107) and human peripheral blood mononuclear cells (PBMC;
1 107). Mice were administered HPN536 daily for 10 days starting on
day 6 via intravenous injection. Tumor size was measured twice weekly and calculated using the following formula: tumor volume (mm3)
(w2 l)/2. Percent tumor growth inhibition (%TGI) was dened as the difference between the mean tumor volume (MTV) of the control
OF2 Clin Cancer Res; 2021
CLINICAL CANCER RESEARCH
Rela
HPN536
An
group and the MTV of the treated group, expressed as a percentage of the MTV of the control group.
Exploratory cynomolgus monkey dose range-ndingstudy The pharmacology, pharmacokinetics, and toxicity of HPN536
were evaluated after a single intravenous bolus dose of 0.1, 1.0, or 10 mg/kg HPN536 in one male and one female cynomolgus monkey per group followed by either a 1- or 3-weekpostdose recovery period. The study followed the protocol and standard operating procedures of the testing facility (Charles River Labo- ratories) and was approved by their IACUC. Pharmacologic activ- ity was evaluated by clinical observations, cytokine assessments, ow cytometry, and evidence of target engagement by histology. Two research electrochemiluminescence assays, a functional assay and an anti-idiotypeassay, were used for measuring HPN536 levels in serum. For the functional assay, HPN536 was captured with biotinylated CD3e and was detected with a sulfo-taggedMSLN. For the anti-idiotypeassay, HPN536 was captured with an anti- idiotype antibody recognizing the anti-albumindomain and was detected with a sulfo-taggedCD3e. Toxicokinetic parameters were estimated using Phoenix WinNonlin pharmacokinetic software. A noncompartmental approach, consistent with the intravenous bolus route of administration, was used for parameter estimation.
Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392
HPN536 an Anti-MSLN/Anti-CD3T-Cell Engager for Solid Tumors
Toxicity endpoints included daily morbidity and mortality, daily clinical observations, weekly body weights, daily food consump- tion, clinical pathology (hematology, clinical chemistry, and coag- ulation), and anatomic pathology (gross necropsy, organ weights, and histopathology).
Results
Production, structure, and biochemical characteristics of
HPN536
Recombinant HPN536 has a molecular weight of approximately
53 kDa. A humanized llama sdAb specic for human MSLN is placed at its N-terminus (Fig. 1A). A humanized llama sdAb specic for human serum albumin (HSA) is placed in the middle of the molecule. The C-terminal end contains a humanized scFv specic for the human CD3e subunit of the TCR complex. GGGGSGGGS linkers connect the three binding domains.
HPN536 is produced by eukaryotic cell culture and secreted as a single, nonglycosylated polypeptide. Stability studies subjecting HPN536 to various stress conditions, including multiple freeze thaw cycles and storage at 4 C and 40 C for 2 weeks, suggest the protein is stable and stress resistant (Supplementary Fig. S1). The high stability of HPN536 ensures limited aggregation, which would otherwise lead to
huMSLN
huCD3e
huALB
A
B
MSLN
ALB
MSLN
CD3
ALB
CD3
In vitro anity
Human KD (nmol/L)
0.21
6.6
6.3
measurements
CynoK D (nmol/L)
1.1
6.2
5.6
Mouse (nmol/L)
210
NB
170
HPN536 binding to MSLN-
HPN536 binding to
expressing OVCAR8 cells
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