Clinical trials are research studies that involve people. Phase 2 multicenter trial of icos agonist monoclonal antibody mab jtx2011 and a ctla4 inhibitor in pd1pdl1 inhibitor experienced adult subjects with nonsmall cell lung cancer or urothelial cancer. These data provided the rationale for development of a high affinity humanized agonist monoclonal antibody to be tested in both mono therapy and in combination with other t cell checkpoints. The clinical trials on this list are studying antiicos agonist antibody gsk3359609. These lead agonist mabs have been shown to be efficacious both as monotherapies in multiple syngeneic tumor models and in combination with an antipd1 antibody. This is a phase 12, open label, multicenter, dose escalation and expansion, firstinhuman fih clinical study to evaluate the safety and tolerability, pk, pd, and preliminary efficacy of the icos agonist monoclonal antibody jtx2011 alone and in combination with nivolumab, ipilimumab, or pembrolizumab in adult subjects with advanced andor. Ky1044, a novel antiicos antibody, elicits long term in. The molecule seems to be important in t cell effector function. Icos expression was also increased on cd8 t cells in irradiated tumors 25.
The promise and challenges of immune agonist antibody. Our lead product candidate, vopratelimab, is a monoclonal antibody that binds to and activates the inducible t cell costimulator icos, a protein on the surface of certain t cells that we believe can stimulate an immune response against cancerous cells. Gsk today announced the start of a phase i clinical trial with gsk3359609, an investigational inducibile tcell costimulator icos agonist antibody. Jun wang, michael beck, jamison grailer, jim hartnett, julia. Jounce therapeutics reports improved pfs and os associated. Jun wang, michael beck, jamison grailer, jim hartnett. Efficacy of antiicos agonist monoclonal antibodies in preclinical. Inducible t cell costimulator icos, a member of the cd28b7 receptor superfamily, is expressed on t cells after t cell receptor engagement with cognate antigen. Ky1044, a novel fully human antiicos antibody has a dual mechanism of action. Firstinclass icos agonist alone or in combination may be effective for advanced cancer. The sequence of administration of ipilimumab and vopratelimab combination in emerge is designed to induce icos hi cd4 t cells with ipilimumab followed by their expansion and sustained activation by vopratelimab. Inducible tcell costimulatory icos receptor agonist. However, under certain circumstances such as following vaccination and ctla4 blockade. Icos is critical for cd40mediated antibody class switching.
Pdf inducible costimulator icos as a potential therapeutic. In preclinical studies, icos agonist monoclonal antibodies mabs have shown to potentiate the effect of inhibitory checkpoint blockade. Jtx2011 is a firstinclass icos agonist antibody that has been demonstrated preclinically to have a tumorcentric dual mechanism of action through stimulation of cd4 t effector cells and depletion of intratumoral t regulatory cells. This molecule, short for inducible tcell costimulator, and also called cd278, is expressed on activated t cells. In mice bearing ct26 tumors, icos agonist antibody. Ky1044, a novel antiicos antibody, elicits long term in vivo. Oral presentation open access efficacy of antiicos agonist. Icos inducible costimulator molecule is a t cell encoded member of the extended b7cd28 superfamily that is upregulated upon early t cell activation. Upon administration, antiicos agonist antibody gsk3359609 targets and binds to icos expressed on tumor infiltrating cd4positive t cells. Inducible tcell costimulator is an immune checkpoint protein that in humans is encoded by the icos gene. Anti icos antibody displays agonist activity in jurkat cell reporter assay with gfp readout a published antagonist anti icos has no agonist activity effect of anti icos mabs on jurkat icos reporter assay. Efficacy of antiicos agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer. Definition of antiicos agonist antibody gsk3359609 nci. Jtxx2011dualmechanismshiftsbalanceoftcellstowardsanti xtumoractivity apc.
Pdf efficacy of antiicos agonist monoclonal antibodies in. T regulatory treg cells as well as preferential reduction in icoshigh tregs in the tumor microenvironment. Firstinclass icos agonist alone or in combination may be. A novel antiox40 agonist antibody with the potential to enhance tumor specific tcell responsiveness, while selectively depleting intratumoral regulatory t cells abstract. Efficacy, safety, and combination strategies with anti icos agonists or antagonists have yet to be specified. Antiicos agonist antibody gsk3359609 semantic scholar. Human clinical and mouse preclinical data support activating icos receptor for antitumor benefit. An agonist antibody may be defined as one which, when tested in a t cell activation assay. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. T regulatory treg cells as well as preferential reduction in icos high tregs in the tumor microenvironment. Targeting negative and positive immune checkpoints with. A dual mechanism of action is intended to activate antigenspecific cd4 t effector cells and selectively deplete intratumoral t regulatory cells.
Preclinicalassessmentofjtx32011, anagonistantibody. Jtx2011 is an agonist monoclonal antibody that targets icos, inducible costimulator of t cells. Efficacy of antiicos agonist monoclonal antibodies in. Phase 2 multicenter trial of icos agonist monoclonal. Antiicos antibody displays agonist activity in jurkat cell reporter assay with gfp readout a published antagonist antiicos has no agonist activity effect of antiicos mabs on jurkat icosreporter assay. Discovery of a pd1 checkpoint agonist antibody for. The isa3 monoclonal antibody reacts with human icos inducible costimulatory molecule, also known as h4, crp1 and ailim.
Gsk presents new data showing promising antitumour activity. Phase 1 safety of icos agonist antibody jtx2011 alone and. Icos costimulation at the tumor site in combination with ctla4. Aug 25, 2004 the inducible costimulator icos, the third member of the cd28cd152 receptor family, is an important costimulatory molecule during the immune response. Icos is a costimulatory receptor that enhances tcell responses and results in an increased anti. Icos agonist antibody specificityfor icos speciescross xreactive agonist activity humanizedrodent antibody higg1fcbackbone 5 jouncetherapeutics2017 donotpost jtx32011. Clinical trials using antiicos agonist antibody gsk3359609. Ncis basic information about clinical trials explains the types and phases of trials and how they are carried.
Gsk presents new data showing promising antitumour. Syngeneic mouse tumor models and human exvivo pbmc and tumor infiltrating lymphocyte culture assays were utilized to evaluate the activity of a murine 7e. Icos expression is induced on t cells within 24 h after stimulation of the tcell receptor. It is well established that nfkb and the upstream kinase pkbakt are highly expressed in chemoresistance tumor cells and play a major role in hampering the. Bristolmyers squibb research and development pipeline. In the absence of agonist antibody or 41bb ligand, the 41bb receptor is not activated and luminescence signal is low. Deng zb1, zhu w, lu cm, shi q, ju sg, ma hb, xu y, zhang xg. Agonist antiicos ab requires both tcr activation and fcr crosslinking. Herein, we described an alternative icos agonist, an oligonucleotidebased aptamer that can be engineered as a bispecific target molecule to deliver icos costimulus at the tumor in situ. Agonists of costimulation in cancer immunotherapy directed. We have generated a panel of antiicos monoclonal antibodies with in vitro agonist properties. An agonist human icos monoclonal antibody that induces t. Human icos has a relative molecular mass of 5560 kda, composed of 27 kda and 29 kda chains.
Phase i clinical trials investigating safety of an investigational medicine in a small number of human subjects. Icosfoxp3 expression varies in human tumour types, showing high expression in head and neck cancers, and low expression in glioblastomaglioma. An agonistic antibody for the inducible tcell costimulator icos. Icos is involved in the interaction between t and bcells ig class switching, and in antibody responses to tcell dependent antigens. Efficacy of antiicos agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer immunotherapeutics. Kehry, gerald manorek, janean fisher, natasha del cid, allison rooks, laurence altobell iii, gregory gold, morena shaw, robert morse,margaret marino, jessiefarah fecteau, and stephen parmley. This stimulates icospositive tcell proliferation, enhances cytotoxic tlymphocyte ctl survival and increases ctlmediated immune responses against tumor cells.
Icos is a tcell coregulatory receptor that provides a costimulatory signal to t cells during antigenmediated activation. The american biotechnology company jounce therapeutics is developing an icos agonist. Agonist anti icos ab fc regions are crosslinked by fc. The bioassay consists of one engineered cell line, 41bb effector cells. Pharmacokineticpharmacodynamic pkpd exposureresponse. Antitumor immunity can be improved by icos targeting therapies, but their mechanism of action remains unclear. Gsk announces start of phase i oncology study with its icos. The rationale behind targeting the icosicos ligand.
Icos is a costimulatory receptor that enhances tcell responses and results in an increased antitumour response from the immune system. Discovery of a pd1 checkpoint agonist antibody for autoimmuneinflammatory disease marilyn r. This study is the first report of the antimurine ox40 agonist antibody ox86, which has subsequently been used in most of the preclinical studies of ox40 agonist antibody. Agonist antiicos ab fc regions are crosslinked by fc. A luciferase reporter integrates signals from both the tcr and icos. A novel antibody targeting icos increases intratumoural. The specificity of this mab was verified by flow cytometry, western blotting, and competition with anti icos mab isa3. Eligible patients pts for hnscc expansion cohorts ec had recurrent or metastatic disease.
Btla agonist antibodies and uses thereof eli lilly and company. Bioassaysfceffectoranalysiscomprehensive may2019 ps356. Cd278 or icos inducible tcell costimulator is a cd28superfamily costimulatory molecule that is expressed on activated t cells. Preclinical rationale for icos agonist igg1 antibody monotherapy efficacy in mouse tumors with high % icos expressing immune cells enhanced efficacy in combination with pd1 and ctla4 inhibitors period of sustained target engagement required for preclinical antitumor efficacy. Preclinical evaluation of a nondepleting, firstinclass. Here we present nonclinical data evaluating icos agonist antibody activity in human and mouse model systems using a different antibody for each species.
In transplanted tumor models, agonist antibodies directed against icos do not exert a powerful immunotherapeutic effect perhaps as a result of predominant cd4 expression and because they do not aid a cytotoxic immune responses. An agonist human icos monoclonal antibody that induces t cell. Gsk3359609 is a humanised igg4 antibody selected for its potent binding, agonist activity through the human icos receptor and lowno tcell depleting effects via antibody dependent cellular toxicity in nonclinical models. Icos is a t cell specific activation molecule and a third member of the cd28ctla4 family. Adc antibody drug conjugate esa erythropoiesisstimulating agent for information on approved uses, refer to approved product labeling. Effs and regulatory tcells t regs, as well as tcell proliferation and survival. Preclinical evaluation of a nondepleting, firstinclass humanized. The addition of agonist antibody or 41bb ligand induces the 41bb pathwayactivated luminescence, which can be detected in a dosedependent manner.
Gsk today announced gsk3359609, an inducible t cell costimulatory icos agonist antibody designed to selectively enhance t cell function, showed promising antitumour activity in combination with pembrolizumab in pd1l1 naive patients with head and neck squamous cell carcinoma hnscc. Immune agonist antibodies face critical test nature. Phase 12 multicenter trial of icos agonist monoclonal. Human icos on activated t cells has potent costimulatory activity for t cell activation and is required for humoral immune responses, in particular for memory b cell and plasma cell generation. Currently, two agonists and one antagonist mab are being evaluated in phase iii trials. Pdf icos inducible costimulator molecule is a t cell encoded member of the extended b7cd28 superfamily that is upregulated upon. Inducible costimulator icos as a potential therapeutic. Mechanistic studies that demonstrate tumor regression is associated with enhanced ratios of cytotoxic cd8regulatory t tregs cells as well as preferential reduction in icos. Oct 11, 2018 the administration of effective amounts of the anti icos antibody alone, or anti icos antibody combined with antipd1 antibody, combined with an antipdl1 antibody, or combined with antictla4 antibody, according to any of the methods provided herein, can result in at least one therapeutic effect, including, for example, reduced tumor growth. The fab regions of the icos ab bind icos on the effector cell to induce activation.
Jtx2011 alone and in combination with antipd1 or anti. A pulsed dose and schedule for vopratelimab, designed to optimize agonist antibody activity, is explored. Over the past 15 years, agonist antibodies against costimulatory receptors including icos, gitr, ox40, cd27 and 41bb have uniformly failed. Functional agonist antipd1 antibodies that downregulate antigenspecific immune responses and lack antagonist activity can be discovered and optimized anb030 is a humanized igg1. Cd278, with potential immune checkpoint inhibitory and antineoplastic activities. Second and thirdgeneration drugs for immunooncology. Icos agonist apt8a enhances t lymphocyte activation in vitro. Jounce therapeutics to present safety and preliminary. Overall, the current pk and nonmonotone pd data provide evidence of gsk3359609 target engagement and. Upon administration, anti icos agonist antibody gsk3359609 targets and binds to icos expressed on tumor infiltrating cd4positive tcells. Quantitative cellbased bioassays to advance immunotherapy. This may provide a benefit for patients having disease states with transient levels of hvem, wherein it may desirable to have a btlamimicking agonist antibody onboard during times when the patient has a reduction in hvem.
Lack of accessibility to monoclonal antibodies agonistic to icos led us to develop an alternative agonist. Singleagentdevelopmentofjtxx2011 supportedbylong xlastingresponseinpreclinicaltumormodels 0 10 20 30 40 0 200 400 600. Nov 22, 2018 this antibody also has a higher binding affinity to btla as compared to hvem binding btla. Anti icos agonist monoclonal antibody humanised igg4.
In contrast, antagonistic antiicos mabs could not only inhibit lymphoid tumour cells expressing icos, but also dampen immunosuppressive tregs. First inhuman study with gsk3359609, an inducible t cell. Phase 12 multicenter trial of icos agonist monoclonal antibody mab jtx2011 alone and in combination with nivolumab, ipilimumab, or pembrolizumab in adult subjects with advanced andor refractory solid tumor malignancies. Therefore, both antagonist and agonist antibodies might be of interest in the targeting icosicosl pathway for cancer treatment. Icos, first identified in humans 20 years ago, is the third member of the cd28 coreceptor family, which are all involved in regulating t cell activation and adaptive immune responses. The unique mechanistic profile of an icos agonist antibody, such as gsk3359609, offers an opportunity to investigate the antitumor potential of targeting a t cell costimulator alone and in combination with other cancer immunotherapies such as pembrolizumab.
Inducible t cell costimulatory icos receptor agonist. Efficacy of anti icos agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer immunotherapeutics. Gsk presents new data showing promising antitumour activity with gsk3359609, an icos receptor agonist, in combination with pembrolizumab in head and neck squamous cell carcinoma hnscc data presented at esmo 2019 support initiation of phase iiiii registrational trial with pembrolizumab in firstline recurrentmetastatic hnscc. Here, we define the role of icos signaling in antitumor immunity using a blocking, nondepleting antibody against icos ligand icos l. Jtx2011, a species crossreactive high affinity humanized agonist monoclonal antibody, has been selected for development. Icos costimulation at the tumor site in combination with. Agonists of costimulation in cancer immunotherapy directed against cd7, ox40, gitr, cd27, cd28, and icos. Mechanistic studies demonstrate that tumor regression is associated with enhanced ratios of cytotoxic cd8. Gsk3359609 is an antiinducible t cell costimulator icos receptor agonist antibody intended for the treatment of cancers of different histology. Icos agonist bioassay icos agonist bioassay icos blocking bioassay cd28 agonist bioassay cd28 blocking bioassay april 2018 corresponding author. The addition of agonist antibody or 41bb ligand induces the 41bb.
Its ligand is icosl, expressed mainly on b cells and dendritic cells. A homodimer of 4757 kda, icos is expressed on activated t cells, has potent costimulatory activity for t cell activation and proliferation and is required for humoral. Chicagojtx2011 an inducible costimulator icos of tcells may be a safe and effective treatment option alone or in combination with nivolumab among patients with heavily pretreated gastric gc and triplenegative breast cancer tnbc. Oral presentation open access efficacy of antiicos. Vopratelimab is an investigational icos agonist monoclonal antibody that results in activation and proliferation of cd4 t effector cells with high levels of icos. This stimulates icospositive tcell proliferation, enhances cytotoxic tlymphocyte ctl survival and increases ctl. Since both cd4 and cd8 t cells upregulate icos with antictla4 treatment, a nondepleting icos agonist antibody gsk335609 was chosen to evaluate the combination. Both antagonist and agonist antibodies are of interest in targeting the icos icos l pathway for cancer treatment. We have therefore developed an icos antibody optimized for agonist activity. Agonistic tcell nondepleting icos antibody strongly. An agonist human icos monoclonal antibody that induces t cell activation and inhibits proliferation of a myeloma cell line.
In some embodiments, an isolated antibody that binds icos is provided, wherein the antibody is an agonist of cd4 t cells such as cd4 t effector teff cells. In some embodiments, an isolated antibody that binds icos is provided, wherein the antibody is an agonist of cd4 t cells such as cd4 teff cells and depletes t regulatory treg cells. Our lead anti icos antibody is currently in indenabling studies and will be tested for activity in solid tumor indications. As a matter of fact, icos agonist and antagonist antibodies for cancer immunotherapy are currently under research in the clinical pipeline. A significant difference is observed for test antibody relative to a cognate isotype control within the dynamic range of the assay is indicative that the antibody acts as an agonist of the icos receptor in that assay. Icos regulates both pro and antiinflammatory cytokine production by effector tcells t. Gsk announces start of phase i oncology study with its. Pdf efficacy of antiicos agonist monoclonal antibodies. Antigitr agonist antibody anti41bb agonist antibody. Preclinical evaluation of jtx2011, an antiicos agonist antibody icos inducible costimulator molecule is a costimulatory molecule and a member of the cd28. Icos costimulation at the tumor site in combination with ctla. Jtx2011 is equally potent across human, rodent, and nonhuman primate species.
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