Cholangiocarcinoma, a malignant neoplasm that arises in the bile duct epithelium, is refractory to conventional therapies such as chemotherapy and radiotherapy. Also, molecular targeted agents that were effective in several types of cancers have not yet been satisfactory in cholangiocarcinoma. There...
Cholangiocarcinoma, a malignant neoplasm that arises in the bile duct epithelium, is refractory to conventional therapies such as chemotherapy and radiotherapy. Also, molecular targeted agents that were effective in several types of cancers have not yet been satisfactory in cholangiocarcinoma. Therefore, new effective therapeutic strategies for cholangiocarcinoma are urgently needed.
L1 cell adhesion molecule (L1CAM, CD171) is aberrantly expressed in cholangiocarcinoma and increased cell proliferation, migration, and resistancy to chemodrugs. High expression of L1CAM correlated with poor prognosis of patient with cholangiocarcinoma. This suggests that L1CAM could serve as a therapeutic target for the cholangiocarcinoma. The aim of this study is thus to evaluate whether an anti-L1CAM human monoclonal antibody has potential as a therapeutic reagent for the treatment of cholangiocarcinoma.
In this study, a human monoclonal antibody (Ab4) that specifically binds to both human and mouse L1CAM was affinity-matured through alanine scanning mutagenesis of complementarity determining regions (CDRs) in heavy and light chain, and Ab4M was constructed. To increase affinity of Ab4M up to sub-nanomolar ranges, random mutagenesis and yeast display technology was applied to the light chain CDR3 of Ab4M. As a result, the final antibody candidate (Ab417) was isolated and its affinity (KD) to human L1CAM and mouse L1CAM was 0.24 nM and 79.16 pM, respectively. Through the affinity-maturation, the affinity of Ab417 to human L1CAM was 92-folds increased relative to that of Ab4, the parental type antibody. Ab417 was evaluated for antigen-binding specificity, pharmacokinetics (PK), tumor targeting, antitumor activity, and toxicity in animal models. Since the Ab417 was cross-reactive to both human and mouse L1CAM, anti-tumor efficacy and toxicity could be assessed in mouse models ahead of non-clinical studies. The half-life of Ab417 was 114 h from the PK study on SD rats. By cholangiocarcinoma xenograft model studies, significant tumor growth inhibition activities were exhibited and combinatorial anti-tumor efficacy was also confirmed when this mAb treated with chemodrugs. Besides the efficacy, safety of Ab417 was proved by conducting a toxicological study in normal mice models.
In addition, other variants derived from Ab417 were constructed to improve the biophysical properties and productivity, and Ab417-H6L2 was constructed which has decreased pI value and increased productivity while its affinity to human L1CAM was retained.
This study demonstrated that the human monoclonal antibody binding to L1CAM has potential for the treatment of cholangiocarcinoma and other L1CAM-expressing cancers.
Cholangiocarcinoma, a malignant neoplasm that arises in the bile duct epithelium, is refractory to conventional therapies such as chemotherapy and radiotherapy. Also, molecular targeted agents that were effective in several types of cancers have not yet been satisfactory in cholangiocarcinoma. Therefore, new effective therapeutic strategies for cholangiocarcinoma are urgently needed.
L1 cell adhesion molecule (L1CAM, CD171) is aberrantly expressed in cholangiocarcinoma and increased cell proliferation, migration, and resistancy to chemodrugs. High expression of L1CAM correlated with poor prognosis of patient with cholangiocarcinoma. This suggests that L1CAM could serve as a therapeutic target for the cholangiocarcinoma. The aim of this study is thus to evaluate whether an anti-L1CAM human monoclonal antibody has potential as a therapeutic reagent for the treatment of cholangiocarcinoma.
In this study, a human monoclonal antibody (Ab4) that specifically binds to both human and mouse L1CAM was affinity-matured through alanine scanning mutagenesis of complementarity determining regions (CDRs) in heavy and light chain, and Ab4M was constructed. To increase affinity of Ab4M up to sub-nanomolar ranges, random mutagenesis and yeast display technology was applied to the light chain CDR3 of Ab4M. As a result, the final antibody candidate (Ab417) was isolated and its affinity (KD) to human L1CAM and mouse L1CAM was 0.24 nM and 79.16 pM, respectively. Through the affinity-maturation, the affinity of Ab417 to human L1CAM was 92-folds increased relative to that of Ab4, the parental type antibody. Ab417 was evaluated for antigen-binding specificity, pharmacokinetics (PK), tumor targeting, antitumor activity, and toxicity in animal models. Since the Ab417 was cross-reactive to both human and mouse L1CAM, anti-tumor efficacy and toxicity could be assessed in mouse models ahead of non-clinical studies. The half-life of Ab417 was 114 h from the PK study on SD rats. By cholangiocarcinoma xenograft model studies, significant tumor growth inhibition activities were exhibited and combinatorial anti-tumor efficacy was also confirmed when this mAb treated with chemodrugs. Besides the efficacy, safety of Ab417 was proved by conducting a toxicological study in normal mice models.
In addition, other variants derived from Ab417 were constructed to improve the biophysical properties and productivity, and Ab417-H6L2 was constructed which has decreased pI value and increased productivity while its affinity to human L1CAM was retained.
This study demonstrated that the human monoclonal antibody binding to L1CAM has potential for the treatment of cholangiocarcinoma and other L1CAM-expressing cancers.
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