Abstract 544P
Background
HER2-directed therapies have improved clinical outcomes for solid cancer patients with HER2 overexpression. Despite this success, it still remains a challenge to cure the HER2 positive cancer patients with resistance to current HER2-directed therapy. Therefore, effective HER2-directed therapy needs to be developed for them, and one approach would be to combine with immunotherapy. 4-1BB (TNFSF9, CD137) is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator to immune cells, especially on primed T and NK cells in tumors.
Methods
We have developed a bispecific antibody (BsAb) which induce tumor-directed T cell activation to overcome the challenges with HER2 resistance. Its activity was determined using cell-based 4-1BB bioassay and co-culture assay with human peripheral blood mononuclear cells (hPBMC). Also, in vivo anti-tumor efficacy of YH32367 (ABL105) was assessed in both HER2-expressing tumor-bearing hPBMC humanized mice and h4-1BB knock-in mice.
Results
A novel HER2/4-1BB BsAb, YH32367 simultaneously targets human epidermal growth factor receptor 2 (HER2) and h4-1BB and binds to both targets. YH32367 exhibited a strong 4-1BB signal activation in HER2-expressing tumor cells such as NCI-N87, JIMT-1 and HCC1954 cells. YH32367 stimulated IFN-γ secretion and thereby inducing tumor cells lysis in co-culture assay with hPBMC and HER2-expressing tumor cells. YH32367 also showed superior efficacies on immune cells activation as well as tumor growth inhibition in both HER2-expressing tumor-bearing hPBMC humanized mice and h4-1BB knock-in mice models compared to the equimolar dosing of trastuzumab and benchmark 4-1BB agonistic antibodies. In particular, even a single dosing of YH32367 at doses of 1, 3 and 10 mg/kg elicited complete tumor regression in most tumors of MC38/hHER2-bearing h4-1BB knock-in mice. Peripheral T cell increase was not observed in these in vivo studies.
Conclusions
In conclusion, YH32367 exhibited potent in vitro and vivo effect through tumor-directed T cell activation. It suggests that YH32367 could be promising to develop for the patients with HER2 positive cancer as an effective HER2-directed therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Yuhan Corporation.
Funding
Has not received any funding.
Disclosure
E. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. H. Chung: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. Y. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. E. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. Y.B. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. Y. Kim: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. J.Y. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. S. Ahn: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. J. Kim: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. K.K. Ahn: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. K. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. W. Son: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. D. Yeom: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. J. Jung: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. J. Won: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. S. Oh: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm.