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| Title | Structural insights into epitope-paratope interactions of a monoclonal antibody targeting CEACAM5-expressing tumors. |
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| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 9377, Year 2024 |
| Publish date | Oct 30, 2024 |
Authors | Anand Kumar / Francis Duffieux / Marie Gagnaire / Chiara Rapisarda / Thomas Bertrand / Alexey Rak / ![]() |
| PubMed Abstract | Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are overexpressed in some tumor types. The antibody-drug conjugate tusamitamab ravtansine specifically recognizes the A3-B3 domains ...Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are overexpressed in some tumor types. The antibody-drug conjugate tusamitamab ravtansine specifically recognizes the A3-B3 domains of human CEACAM5 (hCEACAM5). To understand this specificity, here we map the epitope-paratope interface between the A3-B3 domains of hCEACAM5 (hCEACAM5) and the antigen-binding fragment of tusamitamab (tusa Fab). We use hydrogen/deuterium exchange mass spectrometry to identify the tusa Fab paratope, which involves heavy chain (HC) residues 101-109 and light chain residues 48-54 and 88-104. Using surface plasmon resonance, we demonstrate that alanine variants of HC residues 96-108 abolish binding to hCEACAM5, suggesting that these residues are critical for tusa-Fab-antigen complex formation. The cryogenic electron microscopy structure of the hCEACAM5- tusa Fab complex (3.11 Å overall resolution) reveals a discontinuous epitope involving residues in the A3-B3 domains and an N-linked mannose at residue Asn612. Conformational constraints on the epitope-paratope interface enable tusamitamab to target hCEACAM5 and distinguish CEACAM5 from other CEACAMs. |
External links | Nat Commun / PubMed:39477960 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.11 Å |
| Structure data | EMDB-16279, PDB-8bw0: |
| Chemicals | ![]() ChemComp-NAG: |
| Source |
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Keywords | CELL ADHESION / CEACAM5 / Tusamitamab / Cancer / cryo-EM / small molecular weight / Fab / A3-B3 / human membrane protein |
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homo sapiens (human)
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