Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3
Maria Amann1, Klaus Brischwein, Petra Lutterbuese
1Micromet AG, Munich, Germany.
Abstract:
EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 microg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 microg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development.
Insights
A novel EpCAM-targeting bispecific T-cell engager (BiTE) antibody, muS110, shows significant antitumor activity in mouse models. This EpCAM-specific BiTE antibody demonstrates a promising therapeutic window for cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- Epithelial cell adhesion molecule (EpCAM) is a highly expressed tumor-associated antigen found on various cancer stem cells.
- EpCAM is also present on normal tissues, posing a challenge for targeted immunotherapies.
- Bispecific T-cell engagers (BiTEs) offer a promising approach for cancer immunotherapy.
Purpose of the Study:
- To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct (muS110) in preclinical mouse models.
- To evaluate the antitumor activity and safety profile of muS110.
Main Methods:
- Construction of a murine surrogate of MT110 (muS110) targeting murine EpCAM and CD3.
- Immunohistochemical analysis of EpCAM expression in human and mouse tissues.
- Assessment of muS110's antitumor activity in syngeneic breast and lung cancer mouse models.
- Evaluation of muS110 tolerability through dose escalation studies.
Main Results:
- EpCAM expression patterns were similar between human and mouse tissues.
- MuS110 demonstrated significant antitumor activity at low doses (5 microg/kg) in breast and lung cancer models.
- MuS110 was well-tolerated at high doses (up to 400 microg/kg), indicating a substantial therapeutic window.
- MuS110 exhibited comparable in vitro and in vivo characteristics to the human counterpart, MT110.
Conclusions:
- EpCAM-specific BiTE antibodies, like muS110, possess significant therapeutic potential.
- The established therapeutic window in mice supports further preclinical development of EpCAM-targeting BiTEs.
- MuS110 serves as a valuable preclinical model for human EpCAM-targeting immunotherapies.
