Biotechnology techniques for the development of new tumor specific peptides

Marr, Annabell; Markert, Annette; Altmann, Annette; Askoxylakis, Vasileios; Haberkorn, Uwe

doi:10.1016/j.ymeth.2011.05.002

Cited by 19 publications

(19 citation statements)

References 67 publications

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“…In addition, this approach provides a versatile means for identifying enzymes actually responsible for the in vivo degradation of a particular radiopeptide drug. This information may be essential for the rationale design of new, stabilized radiopeptide analogs but may also have consequences for other peptide drugs, such as peptide-conjugated cytotoxic drugs, optical imaging peptide probes, or peptidic ligands selected by phage display technologies (37).…”

Section: Discussionmentioning

confidence: 99%

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

et al. 2013

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Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice. Methods: The peptide conjugates [DOTA-Ala 1 ]SS14 (DOTA-Ala-Gly-c[Cys-LysAsn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH), PanSB1 (DOTA-PEG 2 -DTyr-Gln-Trp-Ala-Val-bAla-His-Phe-Nle-NH 2 ), and DOTA-MG11 (DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ) were labeled with 111 In by 20 min of heating at an acidic pH. Metabolic stability was studied with high-performance liquid chromatography analysis of blood samples collected 5 min after the injection of the test radiopeptide alone or with PA into mice. Biodistribution was studied after injection of each 111 In-labeled radiopeptide alone or after coinjection of PA in tumor-bearing severe combined immunodeficient (SCID) mice. Results: The amount of intact [ 111 In-DOTA-Ala 1 ] SS14 detected in the mouse circulation at 5 min after the injection of PA increased impressively-from less than 2% to 86%-whereas the uptake in AR4-2J xenografts rose from less than 1 percentage injected dose per gram of tissue (%ID/g) to 14 %ID/g at 4 h after injection. Likewise, the coadministration of PA resulted in a marked increase in the amount of circulating intact 111 In-PanSB1-from 12% to 80%-at 5 min after injection, and radioligand uptake in human PC-3 xenografts in SCID mice escalated from less than 4 %ID/g to greater than 21 %ID/g at 4 h after injection. In a similar manner, the coadministration of PA resulted in an equally impressive increase in intact [ 111 In-DOTA]MG11 levels in the mouse bloodstream-from less than 5% to 70%-at 5 min after injection, leading to a remarkable increase in radiotracer uptake-from 2 %ID/g to greater than 15 %ID/g-in both AR4-2J tumors and A431(CCKR1) tumors (i.e., tumors induced by A431 cells transfected to stably express the human cholecystokinin subtype 2 receptor) in mice at 4 h after injection. This effect was well visualized by SPECT/CT imaging of AR4-2J tumor-bearing mice at 4 h after injection. Conclusion: The results of this study clearly demonstrate that the coadministration of key enzyme inhibitors can effectively prolong the survival of radiolabeled peptides in the circulation, securing their safe transit to the target. This strategy clearly provoked an unprecedented increase in radiolabel accumulation in tumor xenografts in mice; this increase might translate into higher diagnostic sensitivity or improved therapeutic...

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Section: Discussionmentioning

confidence: 99%

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

et al. 2013

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“…They are technically demanding but have two advantages: the ability to handle very large libraries (10 12 -10 13 different sequences or potential molecules) and the possibility of using polymerase chain reaction (PCR) amplification steps to introduce further diversity into the system. Such diversity may be used for the evolution of proteins through iteration of random mutagenesis and selection, a process known as affinity maturation (16,34,35). Both ribosome display and mRNA display have been used to select linear peptides or single-chain antibodies that bind to protein targets with low picomolar affinities.…”

Section: Biotechnology Methods For Identification Of New Ligands: Dismentioning

confidence: 99%

“…During the amplification process, diversity may be further increased with errorprone PCR. High-affinity binding molecules are usually obtained after 3-6 panning rounds (35,38,39).…”

Section: Biotechnology Methods For Identification Of New Ligands: Dismentioning

confidence: 99%

Identification of Ligands and Translation to Clinical Applications

et al. 2017

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Technologic advances in molecular biology and biotechnology are increasingly being used for the development of new tumor-targeting tracers. In oncology, major progress has recently been achieved with peptidic and proteinaceous compounds. The development of new biocompatible molecules relies on the identification and validation of new target structures in close conjunction with the application of novel techniques. The identification of lead compounds by these techniques is followed by the screening of various derivatives of these molecules. Hence, high-throughput methods that generate vast libraries of epitopes have been applied. These libraries are screened to identify the few variants that bind with a high affinity to the target structure. A key feature of this strategy is the large number of candidate molecules that can be identified. Further evaluation and optimization of these molecules requires characterization of structure-function relationships and subsequent improvement with respect to binding, internalization, and biodistribution through a rational design of corresponding analogs.

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“…Phages can be used after modification of their genome so that they present library-encoded peptides on their surface. The common principle is the fusion of peptide libraries with the carboxy-terminal domain of the minor coat protein, pIII [1][2][3]. There are five copies of pIII at each end of the phage virion; pIII, together with the minor coat surface protein pVI, is involved in bacterial cell binding and termination of phage particle assembly during self-assembly of the virions in the host cell.…”

Section: Display Systemsmentioning

confidence: 99%

“…In endoradiotherapy, beta-or alpha-emitting radionuclides are coupled to the carrier molecules which selectively accumulate in the tumor but not in healthy tissues, thereby decreasing radiation toxicity to the peripheral organs [1][2][3]. Alternatively, instead of therapeutically useful alpha or beta isotopes, target-specific carrier molecules may be coupled with either a positron-emitting or gamma isotope and used for the identification of cancerous lesions in the patient.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic and high-throughput approaches for the design of molecular imaging probes and targeted therapeutics

Haberkorn

Mier

Dimitrakopoulou-Strauß

et al. 2014

Clin Transl Imaging

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Recent advances in molecular biology and biotechnology have opened the way for the development of new imaging and treatment modalities based on the biological properties of tissues. In oncology, the major advances have been achieved using peptide and antibody targeting molecules. This approach is based on: (1) the identification of new target structures, and (2) the application of new techniques for the development of new biocompatible molecules. These techniques rely on the identification of lead compounds followed by the screening of various derivatives of these compounds. For this purpose, high-throughput methods have been applied that generate a vast library of possible binders which can be used to screen the whole population for the few variants that show the property of interest. An attractive feature of this strategy is the huge number of candidate molecules that can be used for further evaluation, which consists of the characterization of structure-function relationships and the further improvement by rational design of corresponding analogs.

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Biotechnology techniques for the development of new tumor specific peptides

Cited by 19 publications

References 67 publications

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

“To Serve and Protect”: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting

Identification of Ligands and Translation to Clinical Applications

Mechanistic and high-throughput approaches for the design of molecular imaging probes and targeted therapeutics

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