MEET US AT DCAT WEEK 2018
RGD has a high affinity for αvβ3 integrins overexpressed on tumor neovasculature and on the surface of tumor cells making RGD peptides interesting for the treatment and diagnosis of tumors. When conjugated to imaging agents, RGD peptides can provide high specificity and sensitivity in tumor imaging applications (2). For example, researchers have shown that RGD peptides conjugated to the near-infrared fluorescent dye Cy7 could be useful for noninvasive detection and semi quantification of tumor integrin expression (3). In addition, investigators have designed and tested RGD peptides to serve as targeting molecules that deliver radionuclides to integrins on tumor cells. RGD radiotracers are usually αvβ3 integrin targeted but many cyclic RGD peptide tracers are also able to bind to αvβ5, α5β1, α6β4, α4β1, and αvβ6 integrins and this ability can lead to enhanced tumor uptake. Preclinical and clinical studies have shown that radiolabeled cyclic RGD peptides such as 99mTc-3P-RGD2, 18F-Alfatide-I and 18F-Alfatide-II are useful probes for use in single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging for early cancer detection and for monitoring tumor response to anti-angiogenic treatments in a noninvasive manner (1).
The therapeutic efficacy of anti-cancer drugs can be limited by poor penetration into tumor tissue and by adverse effects on healthy cells. Consequently, interest has turned to tumor-penetrating peptides such as iRGD (cyclic CRGDKRGPDC) that are under development to deliver drugs into extravascular tumor tissue. When injected intravenously, iRGD targets αv integrins expressed on tumor vessels. iRGD peptide is proteolytically cleaved in the tumor exposing what is known as the CendR (C-end Rule) motif at the C-terminus of the peptide. CendR binds to neuropilins, molecules that regulate vascular permeability, to activate a bulk transport pathway through tumor tissue. This transport system allows drugs conjugated to iRGD and free drugs co-administered with iRGD to pass through vessel walls and spread within the tumor tissue (4). In research studies in mice, the co-administration of Gemcitabine, an approved chemotherapy drug for non-small cell lung cancer, with iRGD peptide resulted in enhanced tumor-penetrating ability and therapeutic efficacy of Gemcitabine. Reports from animal studies have shown that iRGD can enhance the intratumoral dissemination and efficacy of Doxorubicin, Paclitaxel and Endostatin when conjugated with these drugs or drug-loaded vehicles. Additional studies have shown that co-administration with iRGD enhances efficacy and accumulation of Paclitaxel, Doxorubicin, Trastuzumab and Cisplatin (5).
RGD peptides also hold promise as antithrombotic drugs. The glycoprotein (GP) IIb/IIIa receptor is a key integrin involved in platelet aggregation and thrombus formation. Fibrinogen is the main ligand that binds to the GP IIb/IIIa receptor and the binding of fibrinogen to this receptor occurs via RGD sequences located in fibrinogen. The binding of fibrinogen to GP IIb/IIIa results in cross-linking between adjacent platelets, which leads to thrombosis (6). Several types of GP IIb/IIIa receptor antagonists exist or are under development to inhibit platelet aggregation including monoclonal antibodies against GP IIb/IIIa and peptide and non-peptide antagonists of GP IIb/IIIa. The peptide antagonists include RGD-containing snake venoms, linear RGD peptides and cyclic RGD or KGD peptides (7). For example, the approved drug Integrilin® (Figure 2), a disulfide-linked cyclic KGD heptapeptide, acts as a competitive antagonist to fibrinogen and reversibly binds to the GP IIb/IIIa receptor. Several regulatory authorities have approved Integrilin® for the treatment of angina, acute coronary syndrome and myocardial infarction.
Figure 2 Eptifibatide, a GP IIb/IIIa receptor antagonist, Bachem H-6654
RGD peptides are widely studied for tissue engineering applications. Synthetic materials used in orthopedic and dental treatments often have useful properties such as 3-D architecture and mechanical strength but these materials do not support strong cell adhesion without the addition of an adhesive factor (8). Immobilization of RGD on the material’s surface helps increase cell adhesion and promotes new tissue formation. Researchers have studied attaching RGD to oxide-coated metals and titanium surfaces in order to enhance implant bone healing (2). In addition, RGD may lead to a biomimetic approach for cornea repair and other tissue needs. For example, researchers are developing an RGD-coupled silk protein-biomaterial to replicate native corneal stromal tissue architecture. Gil et al. reported that tissue-engineered cornea silk biomaterials replicated native corneal stromal lamellar architecture with the appropriate corneal stromal phenotypes and aligned collagen fibril lamellae in culture. The RGD coupling in this application enhanced cell attachment, proliferation, alignment and expression of corneal stroma markers (9).
Further study and development of RGD peptides in the fields of oncology, thrombosis and tissue engineering may lead to improved cancer treatments and imaging, antithrombotic drugs and novel tissue-engineering applications. Bachem offers over 50 different RGD peptides and analogs including many cyclic RGD peptides and a Tide FluorTM labelled RGD peptide to support researchers exploring these areas.
(1) S. Liu, Radiolabeled cyclic RGD peptide bioconjugates as radiotracers targeting multiple integrins, Bioconjug. Chem., 26(18), 1413-1438 (2016)
(2) F. Wang et al., The functions and applications of RGD in tumor therapy and tissue engineering, Int. J. Mol. Sci., 14(7), 13447–13462 (2013)
(3) Y. Wu et al., Near-infrared fluorescence imaging of tumor integrin alpha v beta 3 expression with Cy7-labeled RGD multimers, Mol. Imaging Biol., 8(4), 226-236 (2006)
(4) K. Sugahara et al., Tumor-penetrating iRGD peptide inhibits metastasis, Mol. Cancer Ther., 14(1), 120-128 (2015)
(5) Q. Zhang et al., A novel strategy to improve the therapeutic efficacy of gemcitabine for non-small cell lung cancer by the tumor-penetrating peptide iRGD, PLoS One, 10(6), (2015)
(6) T.A. Meadows and D.L. Bhatt, Clinical aspects of platelet inhibitors and thrombus formation, Circ. Res., 100(9), 1261-1275 (2007)
(7) A.I. Schafer, Antiplatelet therapy with glycoprotein IIb/IIIa receptor inhibitors and other novel agents, Tex. Heart Inst. J., 24(2), 90-96 (1997)
(8) S. Bellis, Advantages of RGD peptides for directing cell association with biomaterials, Biomaterials, 32(18), 4205-4210 (2011)
(9) E. Gil et al., Helicoidal multi-lamellar features of RGD-functionalized silk biomaterials for corneal tissue engineering, Biomaterials, 31(34), 8953-8963 (2010)
Some RGD-based drugs work by inhibiting integrin activity with RGD peptides or RGD mimetics while others are designed to take advantage of the RGD sequence’s affinity for integrins instead of blocking it. For example, researchers have conjugated anti-cancer drugs with RGD to utilize the sequence as a homing peptide to help increase drug potency and reduce toxicity. A notable RGD-based drug success is Integrilin® (eptifibatide), an RGD mimetic. Approved by the US Food and Drug Administration (FDA) in 1998, Integrilin® is a treatment for angina, acute coronary syndrome and myocardial infarction. Currently, there are a number of RGD-based drugs and imaging agents in clinical development as shown in Table 1.
|Product Name||Active Ingredient||Indications||Highest Phase||Companies|
|AH111585||fluciclatide f 18||Solid Tumors||Phase II||GE Healthcare|
|DNX-2401||tasadenoturev||Ovarian Cancer, Anaplastic Astrocytoma, Glioblastoma Multiforme (GBM), Oligodendroglioma, Ependymoma, Gliosarcoma, Pediatric Diffuse Intrinsic Pontine Glioma, Recurrent Glioblastoma Multiforme (GBM), Recurrent Malignant Glioma||Phase II||DNAtrix Inc; Alcyone Lifesciences; Merck & Co Inc; VectorLogics Inc; University of Texas MD Anderson Cancer Center|
|EG-Decorin||Diabetic Foot Ulcers, Pressure Ulcers||Phase II||EyeGene Inc; Huons Global Co Ltd|
|EG-Mirotin||Age Related Macular Degeneration, Diabetic Retinopathy, Retinopathy Of Prematurity||Phase II||EyeGene Inc|
|Rh-RGD-Hirudin||N/A||Thrombosis||Phase II||Simcere Pharmaceutical Group|
|SF1126||Breast Cancer, Prostate Cancer, Glioma, Renal Cell Carcinoma, Non-Small Cell Lung Cancer, Colorectal Cancer, Lymphoma, Chronic Lymphocytic Leukemia (CLL), Pancreatic Cancer, Gastrointestinal Stromal Tumor (GIST), Hepatocellular Carcinoma, Neuroblastoma, Recurrent Head And Neck Cancer Squamous Cell Carcinoma, Refractory Multiple Myeloma, Relapsed Multiple Myeloma||Phase II||SignalRx Pharmaceuticals Inc; Semafore Pharmaceuticals, Inc; Technomark Life Sciences|
Phase II Candidates
GE Healthcare is developing AH111585, [18F] Fluciclatide, as an imaging agent for the diagnosis of solid tumors. [18F] Fluciclatide is an [18F]-labeled RGD tracer designed to image tumor vasculature. In 2013, GE Healthcare completed a Phase II trial that assessed the ability of AH111585 to detect tumors and angiogenesis by [18F] AH-111585 PET Imaging (1).
DNX-2401 is under development by DNAtrix for the treatment of glioblastoma, ovarian cancer and other cancers. This Phase II drug candidate is an oncolytic virus immunotherapy that selectively replicates within and kills tumor cells expressing the RGD-binding integrins, αvβ3 or αvβ5 integrins. In 2016, DNAtrix and Merck & Co. initiated a Phase II trial of DNX-2401 in combination with Keytruda® (pembrolizumab), Merck’s anti-PD-1 therapy, for the treatment of recurrent glioblastoma. Also in 2016, the European Medicines Agency (EMA) granted Priority Medicines designation to DNX-2401 for the treatment of recurrent glioblastoma (2).
EyeGene and Huons Global are developing EG-Decorin for the treatment of pressure sores and diabetic foot ulcers. EG-Decorin is a recombinant peptide from human derived from human metalloprotease ADAM 15 that contains RGD. This product candidate is a topical ointment that induces the formation of normal blood vessels and promotes wound healing. In 2013, Huons Global announced that the Korean Food and Drug Administration gave their approval for EyeGene to conduct Phase I/II clinical trials of EG-Decorin for the treatment of pressure ulcers (1).
In addition to EG-Decorin, EyeGene is developing EG-Mirotin for the treatment of diabetic retinopathy. EG-Mirotin is an RGD containing recombinant peptide derived from human metalloprotease ADAM 15 that promotes healthy and stable blood vessel formation. In 2017, EyeGene registered a Phase IIa trial with the EU Clinical Trial Registry to study the efficacy of EG-Motrin in multiple doses on diabetic macular edema in diabetic retinopathy patients (2).
Simcere Pharmaceutical Group is developing Rh-RGD-Hirudin for the treatment of thrombosis. This drug candidate consists of native hirudin, a thrombin inhibitor found in the salivary glands of the leech Hirudo medicinalis, fused to the RGD tripeptide. Rh-RGD-Hirudin is bi-functional and acts as an anti-thrombin agent and an inhibitor of platelet aggregation (3). As of 2011, Rh-RGD-Hirudin was in Phase II development; however, no further development has been reported (2).
SF1126 is a prodrug under development by SignalRx Pharmaceuticals for the treatment of cancers. The prodrug consists of LY294002, a PI3K inhibitor, attached via a cleavable linker to SF1174, a vascular targeting RGD tetrapeptide. The RGD tetrapeptide selectively binds to cell surface integrins upon which SF1126 is hydrolyzed to the active drug, LY294002 (1). In 2015, the company registered a Phase II trial with the US National Institutes of Health to study the safety and efficacy of SF1126 in patients with recurrent or progressive squamous cell carcinoma of the head and neck and mutations in PIK3CA gene and/or PI-3 Kinase pathway genes (2).
There are also several RGD-based drug candidates in the preclinical stage of development. Iceni Pharmaceuticals is developing Cilcane (cilengitide) for the treatment of multiple myeloma and breast cancer and plans to start Phase I/II trials in multiple myeloma patients. Cilengitide was under development by Merck KGaA but Merck discontinued their cilengitide program after a Phase III CENTRIC trial of cilengitide failed to meet its primary endpoint. Other companies such as TRIM-edicine, DNATtrix, AAVP Biosystems, Orum Therapeutics and Steba Biotech are developing RGD-based cancer treatments. In addition, Adienne Pharma & Biotech is developing an RGD-based drug candidate for the treatment of ischemia reperfusion injury.
Many companies are working to harness the potential of RGD-based therapeutics and imaging agents. To support discovery and research efforts, Bachem offers a wide range of RGD research peptides and analogs. Bachem also provides a comprehensive custom peptide synthesis service and the production of peptide-based new chemical entities.
(1) Medtrack (2018)
(2) Global Data (2018)
(3) W. Mo et al., A novel hirudin derivative characterized with anti-platelet aggregations and thrombin inhibition, J. Thromb. Thrombolysis. 28(2), 230-237 (2009)
What is your official job title at Bachem?
How long have you been with Bachem? Where did you work before Bachem?
I started working for Bachem in April 1998. Previously, I was working at a textile company as a textile finisher.
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I like Yoga, to read, to play the piccolo and to spend time with my two grandsons.
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Thank you very much Barbara.
Interesting news about peptides in basic research and pharmaceutical development:
Biologists’ new peptide could fight many cancers-Massachusetts Institute of Technology
Throwing a molecular wrench into gene control machine leads to ‘melting away’ of leukemia-PR Newswire