HAb18G/CD147を標的とする低免疫原性かつ細胞傷害活性を有する新規抗体フラグメントの開発
The murine monoclonal antibody fragment HAb18-F(ab')2, used as a radioimmunological agent against hepatocellular carcinoma (HCC), elicited human anti-mouse antibody (HAMA) responses in certain patients, restricting its clinical applicability. To address this limitation, HAb18 was humanized via variable domain resurfacing guided by the three-dimensional Fv structure. Three framework residues in HAb18scFv were substituted with human equivalents based on surface accessibility and hydrogen-bonding potential within the homology-modeled Fv. The resulting construct, (HAb18-huscFv)2-Fc, showed markedly reduced reactivity against sera from HAMA-positive patients while retaining antigen specificity and comparable binding affinity (KD = 1.5 × 10⁻⁹ M) relative to the parental antibody. Furthermore, the humanized fragment demonstrated effective antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), suggesting it may offer improved clinical utility through lower immunogenicity and added effector functions.
Humanization of surface-exposed framework residues in the Fv domain reduced HAMA immunogenicity, while fusion with human IgG1 Fc enabled effector functions including ADCC and CDC-mediated cytotoxicity against HCC cells.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/19377306