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  • 1.
    Ekerljung, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    EGFR- and HER2-Binding Affibody Molecules: Cellular studies of monomeric, dimeric and bispecific ligands2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Abnormal expression and signaling of the ErbB receptors is associated with the development and progression of several forms of cancer. In this thesis, new ErbB-targeting affibody molecules are evaluated regarding their cellular effects in vitro. Since ligand binding to an ErbB receptor might have an impact on the cell it is important to be aware of these effects as they may have consequences for the continued growth of the tumor when used in vivo. The affibody molecules are intended for tumor targeting with the prospect of clinical use in imaging or therapy.

    Three types of affibody molecules were studied, HER2-binding, EGFR-binding and bispecific binders that target both EGFR and HER2. The HER2-targeting (ZHER2:342)2 showed promising characteristics. It sensitized SKBR-3 cells to irradiation and decreased cell growth to the same extent as the clinically approved antibody Herceptin. The monomeric version, ZHER2:342, did not induce any large effects on intracellular signaling or biological outcome. This makes (ZHER2:342)2 interesting for therapy purposes, while ZHER2:342 may be better suited for imaging.

    The bispecific affibody molecules were all able to simultaneously bind to both EGFR and HER2, but none of the six constructs resulted in any large effects on cellular outcome. Interestingly, all three monovalent binders are more functional when positioned at the N-terminal part of the construct and the (S4G)3 linker renders higher affinity of the bispecific binders compared to (G4S)3. Tumors that co-express several ErbB receptors are often more aggressive and associated with a worse prognosis, suggesting that the total ErbB expression pattern might be more informative than the expression level of one receptor regarding cancer prognosis and prediction of response to targeted therapies. Bispecific ligands could thus be used as imaging agents with prognostic value. Another aspect of dual targeting is the possibility of increased tumor specificity since tumors are more likely than healthy tissue to express high amounts of two receptors.

    Delarbeten
    1. Effects of HER2-binding affibody molecules on intracellular signaling pathways
    Öppna denna publikation i ny flik eller fönster >>Effects of HER2-binding affibody molecules on intracellular signaling pathways
    2006 (Engelska)Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 27, nr 4, s. 201-210Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: HER2, which is overexpressed in 25-30% of human breast cancers, is a tyrosine kinase receptor critical for the signal transduction network that regulates proliferation, migration and apoptosis of cells. METHOD: We report the effects of two novel HER2-binding affibody molecules (Affibody), (ZHER2:4)2 and ZHER2:342, on intracellular signal transduction pathways (Erk1/2, Akt and PLCgamma1) using quantitative immunoblotting techniques and their biological effects in cell culture. The clinically approved antibody trastuzumab (Herceptin) was used as reference substance. RESULTS: Our data showed that, although all substances target HER2, the effects on the receptor and signaling molecules differed. For example, HER2 phosphorylation was induced by trastuzumab and (ZHER2:4)2 but inhibited by ZHER2:342. The effects these substances had on signal transduction correlated to some degree with changes in growth and migration, e.g. (ZHER2:4)2 stimulated phosphorylation of Erk1/2 and PLCgamma1, as well as growth and migration, while ZHER2:342 did not. ZHER2:342 even inhibited phosphorylation of PLCgamma1 and migration. CONCLUSION: Our data suggest that ZHER2:342 is a promising small agent (7 kDa) that may be used as an alternative, or complement, to trastuzumab. If radiolabelled, it can hopefully also be used for HER2 imaging and radionuclide therapy.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-130677 (URN)10.1159/000093023 (DOI)16651854 (PubMedID)
    Tillgänglig från: 2010-09-10 Skapad: 2010-09-10 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    2. Dimeric HER2-specific affibody molecules inhibit proliferation of the SKBR-3 breast cancer cell line
    Öppna denna publikation i ny flik eller fönster >>Dimeric HER2-specific affibody molecules inhibit proliferation of the SKBR-3 breast cancer cell line
    Visa övriga...
    2008 (Engelska)Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 377, nr 2, s. 489-494Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    HER2-specific affibody molecules in different formats have previously been shown to be useful tumor targeting agents for radionuclide-based imaging and therapy applications, but their biological effect on tumor cells is not well known. In this study, two dimeric ((ZHER2:4)2 and (ZHER2:342)2) and one monomeric (ZHER2:342) HER2-specific affibody molecules are investigated with respect to biological activity. Both (ZHER2:4)2 and (ZHER2:342)2 were found to decrease the growth rate of SKBR-3 cells to the same extent as the antibody trastuzumab. When the substances were removed, the cells treated with the dimeric affibody molecules continued to be growth suppressed while the cells treated with trastuzumab immediately resumed normal proliferation. The effects of ZHER2:342 were minor on both proliferation and cell signaling. The dimeric (ZHER2:4)2 and (ZHER2:342)2 both reduced growth of SKBR-3 cells and may prove therapeutically useful either by themselves or as carriers of radionuclides or other cytotoxic agents.

    Nyckelord
    Affibody molecule, Akt, Erk, HER2, Proliferation, Trastuzumab
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-100038 (URN)10.1016/j.bbrc.2008.10.027 (DOI)000261301600031 ()18930032 (PubMedID)
    Tillgänglig från: 2009-03-24 Skapad: 2009-03-24 Senast uppdaterad: 2018-12-04
    3. The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells
    Öppna denna publikation i ny flik eller fönster >>The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells
    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11, s. e49579-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We have previously shown that the HER2-specific affibody molecule (ZHER2:342)2 inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (ZHER2:342)2 sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (ZHER2:342)2 and 8 Gy (S8Gy 0.006) was decreased by a factor of 4 compared to the untreated (S8Gy 0.023). The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (ZHER2:342)2. Treatment by (ZHER2:342)2 strongly increased the levels of dimerized and phosphorylated HER2 already after 5 minutes of stimulation. The monomeric ZHER2:342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

    Nyckelord
    HER2, Affibody molecule, receptor dimerization, receptor phosphorylation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Biomedicinsk strålningsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-160169 (URN)10.1371/journal.pone.0049579 (DOI)000311151900167 ()23166716 (PubMedID)
    Tillgänglig från: 2011-10-19 Skapad: 2011-10-17 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    4. Effects of an EGFR-binding affibody molecule on intracellular signaling pathways
    Öppna denna publikation i ny flik eller fönster >>Effects of an EGFR-binding affibody molecule on intracellular signaling pathways
    Visa övriga...
    2010 (Engelska)Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 36, nr 4, s. 967-972Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Effects on intracellular signaling were studied in cells treated with the affibody molecule (Z(EGFR:955))(2) that targets the epithelial growth factor receptor (EGFR). EGFR is over-expressed in many types of cancers and plays a fundamental role in cell signaling and it is of interest to find targeting agents capable of blocking the receptor. The clinically approved antibody cetuximab (Erbitux (R)) and the natural ligand EGF were included as reference molecules. Two EGFR-rich cell lines, A-431 and U-343, were exposed to the three targeting agents and lysed. The cell lysates were immunoprecipitated with the receptors, or directly separated by SDS-Pace. Autophosphorylation of the receptors and phosphorylation of the downstream signaling proteins Erk and Akt, were evaluated by Western blotting. Although the three different agents compete for the same binding site on EGFR, they influenced the signaling differently. The affibody molecule did not induce autophosphorylation of EGFR or my other receptor in the EGFR-family but, in spite of this, induced phosphorylation of Erk in both cell lines and Akt in the A-431 cells. Thus, the results suggest that the signaling pattern induced by (Z(EGFR:955))(2) is only partly similar to that induced by cetuximab. This makes the affibody molecule a potentially interesting alternative to cetuximab for EGFR-targeted therapy since it might give different therapy-related effects on tumor cells and different side effects on normal tissues.

    Nyckelord
    A-431, affibody, Akt, epithelial growth factor receptor, Erk, signaling, U-343
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97201 (URN)10.3892/ijo_00000576 (DOI)000275794300027 ()
    Tillgänglig från: 2008-04-29 Skapad: 2008-04-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Generation and Evaluation of Bispecific Affibody Molecules for Simultaneous Targeting of EGFR and HER2
    Öppna denna publikation i ny flik eller fönster >>Generation and Evaluation of Bispecific Affibody Molecules for Simultaneous Targeting of EGFR and HER2
    Visa övriga...
    2012 (Engelska)Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, nr 9, s. 1802-1811Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Co-expression of several ErbB receptors has been found in many cancers and has been linked with increased aggressiveness of tumors and a worse patient prognosis. This makes the simultaneous targeting of two surface receptors by using bispecific constructs an increasingly appreciated strategy. Here we have generated six such bispecific targeting proteins, which each comprising two monomeric affibody molecules with specific binding to either of the two human epidermal growth factor receptors, EGFR and HER2, respectively. The bispecific constructs were designed with (i) alternative positioning (N- or C-terminal) of the different affibody molecules, (ii) two alternative peptide linkers (Gly4Ser)3 or (Ser4Gly)3, and (iii) affibody molecules with different affinity (nanomolar or picomolar) for HER2. Using both Biacore technology and cell binding assays it was demonstrated that all six constructs could bind simultaneously to both their target proteins. N-terminal positioning of the monomeric affibody molecules was favorable to promote the binding to respective target. Interestingly, bispecific constructs containing the novel (Ser4Gly)3 linker displayed a higher affinity in cell binding, as compared to constructs containing the more conventional linker, (Gly4Ser)3. It could further be concluded that bispecific constructs (but not the monomeric affibody molecules) induced dimerization and phosphorylation of EGFR in SKBR3 cells, which express fairly high levels of both receptors. It was also investigated whether the bispecific binding would influence cell growth or sensitize cells for ionizing radiation, but no such effects were observed.

    Nyckelord
    HER2, EGFR, bispecifik, dual targeting
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Biomedicinsk strålningsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-160172 (URN)10.1021/bc3000645 (DOI)000308833600011 ()
    Tillgänglig från: 2011-10-19 Skapad: 2011-10-17 Senast uppdaterad: 2018-12-04
  • 2.
    Ekerljung, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11, s. e49579-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that the HER2-specific affibody molecule (ZHER2:342)2 inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (ZHER2:342)2 sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (ZHER2:342)2 and 8 Gy (S8Gy 0.006) was decreased by a factor of 4 compared to the untreated (S8Gy 0.023). The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (ZHER2:342)2. Treatment by (ZHER2:342)2 strongly increased the levels of dimerized and phosphorylated HER2 already after 5 minutes of stimulation. The monomeric ZHER2:342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  • 3.
    Ekerljung, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Wållberg, Helena
    Division of Molecular Biotechnology, School of Biotechnology, Royal Institute of Technology (KTH).
    Sohrabian, Azita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Friedman, Mikaela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Frejd, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Ståhl, Stefan
    Division of Molecular Biotechnology, School of Biotechnology, Royal Institute of Technology (KTH).
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Generation and Evaluation of Bispecific Affibody Molecules for Simultaneous Targeting of EGFR and HER22012Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, nr 9, s. 1802-1811Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Co-expression of several ErbB receptors has been found in many cancers and has been linked with increased aggressiveness of tumors and a worse patient prognosis. This makes the simultaneous targeting of two surface receptors by using bispecific constructs an increasingly appreciated strategy. Here we have generated six such bispecific targeting proteins, which each comprising two monomeric affibody molecules with specific binding to either of the two human epidermal growth factor receptors, EGFR and HER2, respectively. The bispecific constructs were designed with (i) alternative positioning (N- or C-terminal) of the different affibody molecules, (ii) two alternative peptide linkers (Gly4Ser)3 or (Ser4Gly)3, and (iii) affibody molecules with different affinity (nanomolar or picomolar) for HER2. Using both Biacore technology and cell binding assays it was demonstrated that all six constructs could bind simultaneously to both their target proteins. N-terminal positioning of the monomeric affibody molecules was favorable to promote the binding to respective target. Interestingly, bispecific constructs containing the novel (Ser4Gly)3 linker displayed a higher affinity in cell binding, as compared to constructs containing the more conventional linker, (Gly4Ser)3. It could further be concluded that bispecific constructs (but not the monomeric affibody molecules) induced dimerization and phosphorylation of EGFR in SKBR3 cells, which express fairly high levels of both receptors. It was also investigated whether the bispecific binding would influence cell growth or sensitize cells for ionizing radiation, but no such effects were observed.

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