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TitleBispecific antibody-antigen complex structures reveal activity enhancement by domain rearrangement.
Journal, issue, pagesCell Rep, Vol. 44, Issue 7, Page 115965, Year 2025
Publish dateJul 22, 2025
AuthorsKyohei Sato / Shiro Uehara / Atsushi Tsugita / Mayuka Ishii / Shieru Ishiyama / Atsushi Maejima / Ishin Nakahara / Misae Nazuka / Takashi Matsui / Gatsogiannis Christos / Takeshi Yokoyama / Izumi Kumagai / Koki Makabe / Ryutaro Asano / Yoshikazu Tanaka /
PubMed AbstractBispecific antibodies (BsAbs) have been developed as anti-cancer drugs that accumulate activated T cells on cancer cells by bridging the antigens present in each cell. Ex3 is a diabody-type BsAb ...Bispecific antibodies (BsAbs) have been developed as anti-cancer drugs that accumulate activated T cells on cancer cells by bridging the antigens present in each cell. Ex3 is a diabody-type BsAb composed of an anti-epidermal growth factor receptor (EGFR) antibody and an anti-CD3 antibody. In the design of Ex3, the LH-type domain order (Ex3LH) is shown to have more than 100-fold greater anti-cancer activity than the HL-type domain order (Ex3HL). To understand this phenomenon of activity enhancement by domain-order rearrangement, we report here cryoelectron microscopy (cryo-EM) structures of both Ex3HL and Ex3LH in complex with EGFR and CD3. A structural comparison of the HL and LH types reveals that the domain rearrangement leads to drastic structural changes and that the avoidance of steric hindrance by a favorable bridging angle on the cell surface is the fundamental mechanism for this activity enhancement.
External linksCell Rep / PubMed:40664209
MethodsEM (single particle)
Resolution2.93 - 3.91 Å
Structure data

60764

9ip7

EMDB-60764, PDB-9ip7:
Local refinement structure of sEGFR and 528 Fv (from HL-type bispecific diabody Ex3) complex
Method: EM (single particle) / Resolution: 3.21 Å

60765

9ip8

EMDB-60765: HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (closed conformation)
PDB-9ip8: Poly-alanine model for HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (closed conformation)
Method: EM (single particle) / Resolution: 3.91 Å

60766

9ip9

EMDB-60766: HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (middle conformation)
PDB-9ip9: Poly-alanine model for HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (middle conformation)
Method: EM (single particle) / Resolution: 3.64 Å

60767

9ipa

EMDB-60767: HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (open conformation)
PDB-9ipa: Poly-alanine model for HL-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (open conformation)
Method: EM (single particle) / Resolution: 3.85 Å

60768

9ipb

EMDB-60768, PDB-9ipb:
Local refinement structure of sEGFR and 528 Fv (from LH-type bispecific diabody Ex3) complex
Method: EM (single particle) / Resolution: 2.93 Å

60769

9ipc

EMDB-60769: LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (closed conformation)
PDB-9ipc: Poly-alanine model for LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (closed conformation)
Method: EM (single particle) / Resolution: 3.4 Å

60770

9ipd

EMDB-60770: LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (middle conformation)
PDB-9ipd: Poly-alanine model for LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (middle conformation)
Method: EM (single particle) / Resolution: 3.29 Å

60771

9ipe

EMDB-60771: LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (open conformation)
PDB-9ipe: Poly-alanine model for LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in ternary complex with sEGFR and CD3gamma-epsilon (open conformation)
Method: EM (single particle) / Resolution: 3.31 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • synthetic consturct (others)
KeywordsANTITUMOR PROTEIN/IMMUNE SYSTEM / bispecific antibody / diabody / EGFR / HL / Ex3 / 528 / local refinement / ANTITUMOR PROTEIN / ANTITUMOR PROTEIN-IMMUNE SYSTEM complex / CD3 / ternary complex / OKT3 / LH

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