Bogen, Jan P. ; Hinz, Steffen C. ; Grzeschik, Julius ; Ebenig, Aileen ; Krah, Simon ; Zielonka, Stefan ; Kolmar, Harald (2024)
Dual Function pH Responsive Bispecific Antibodies for Tumor Targeting and Antigen Depletion in Plasma.
In: Frontiers in Immunology, 2019, 10
doi: 10.26083/tuprints-00015735
Artikel, Zweitveröffentlichung, Verlagsversion
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Kurzbeschreibung (Abstract)
Shedding of membrane-bound cell surface proteins, where the extracellular domain is released and found in the circulation is a common phenomenon. A prominent example is CEACAM5 (CEA, CD66e), where the shed domain plays a pivotal role in tumor progression and metastasis. For treatment of solid tumors, the presence of the tumor-specific antigen in the plasma can be problematic since tumor-specific antibodies might be intercepted by the soluble antigen before invading their desired tumor target area. To overcome this problem, we developed a generic procedure to generate bispecific antibodies, where one arm binds the antigen in a pH-dependent manner thereby enhancing antigen clearance upon endosomal uptake, while the other arm is able to target tumor cells pH-independently. This was achieved by incorporating pH-sensitive binding modalities in the common light chain IGKV3-15*01 of a CEACAM5 binding heavy chain only antibody. Screening of a histidine-doped light chain library using yeast surface display enabled the isolation of pH-dependent binders. When such a light chain was utilized as a common light chain in a bispecific antibody format, only the respective heavy/light chain combination, identified during selections, displayed pH-responsive binding. In addition, we found that the altered common light chain does not negatively impact the affinity of other heavy chain only binders toward their respective antigen. Our strategy may open new avenues for the generation of bispecifics, where one arm efficiently removes a shed antigen from the circulation while the other arm targets a tumor marker in a pH-independent manner.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Bogen, Jan P. ; Hinz, Steffen C. ; Grzeschik, Julius ; Ebenig, Aileen ; Krah, Simon ; Zielonka, Stefan ; Kolmar, Harald |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | Dual Function pH Responsive Bispecific Antibodies for Tumor Targeting and Antigen Depletion in Plasma |
| Sprache: | Englisch |
| Publikationsjahr: | 5 November 2024 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 9 August 2019 |
| Ort der Erstveröffentlichung: | Lausanne |
| Verlag: | Frontiers Media S.A. |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Frontiers in Immunology |
| Jahrgang/Volume einer Zeitschrift: | 10 |
| Kollation: | 13 Seiten |
| DOI: | 10.26083/tuprints-00015735 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/15735 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung DeepGreen |
| Kurzbeschreibung (Abstract): | Shedding of membrane-bound cell surface proteins, where the extracellular domain is released and found in the circulation is a common phenomenon. A prominent example is CEACAM5 (CEA, CD66e), where the shed domain plays a pivotal role in tumor progression and metastasis. For treatment of solid tumors, the presence of the tumor-specific antigen in the plasma can be problematic since tumor-specific antibodies might be intercepted by the soluble antigen before invading their desired tumor target area. To overcome this problem, we developed a generic procedure to generate bispecific antibodies, where one arm binds the antigen in a pH-dependent manner thereby enhancing antigen clearance upon endosomal uptake, while the other arm is able to target tumor cells pH-independently. This was achieved by incorporating pH-sensitive binding modalities in the common light chain IGKV3-15*01 of a CEACAM5 binding heavy chain only antibody. Screening of a histidine-doped light chain library using yeast surface display enabled the isolation of pH-dependent binders. When such a light chain was utilized as a common light chain in a bispecific antibody format, only the respective heavy/light chain combination, identified during selections, displayed pH-responsive binding. In addition, we found that the altered common light chain does not negatively impact the affinity of other heavy chain only binders toward their respective antigen. Our strategy may open new avenues for the generation of bispecifics, where one arm efficiently removes a shed antigen from the circulation while the other arm targets a tumor marker in a pH-independent manner. |
| Freie Schlagworte: | antibody discovery, bispecific antibodies, common light chain, recycling antibodies, yeast display, CEACAM5 |
| ID-Nummer: | Artikel-ID: 1892 |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-157352 |
| Zusätzliche Informationen: | Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 05 Nov 2024 13:18 |
| Letzte Änderung: | 06 Nov 2024 09:23 |
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| Suche nach Titel in: | TUfind oder in Google |
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