TY - JOUR
T1 - An IgE antibody targeting HER2 identified by clonal selection restricts breast cancer growth via immune-stimulating activities
AU - Palhares, Lais C G F
AU - Grandits, Melanie
AU - Stoker, Katie
AU - Chauhan, Jitesh
AU - Sow, Heng Sheng
AU - Fruhwirth, Gilbert O
AU - Tsoka, Sophia
AU - Birtley, James
AU - Partington, Leanne
AU - Wilson, Tim
AU - Hardaker, Elizabeth
AU - Karagiannis, Sophia N
AU - Bax, Heather J
AU - FitzGerald, Kevin
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/2/12
Y1 - 2025/2/12
N2 - BACKGROUND: Tumor-targeting IgE antibodies have elicited potent tumor-restricting effects by recruiting immune effector mechanisms. However, a dedicated platform for the generation, selection and evaluation of novel IgEs based on target antigen recognition and functional profiles has not been reported.METHODS: By establishing an IgE class antibody therapeutic design platform to allow selection of lead candidates, we generated a panel of IgEs recognising the human epidermal growth factor receptor 2 (HER2), overexpressed in 15-20% of breast cancers. From 1840 phage display-generated variable region sequences panned against HER2, we engineered 30 full length IgE antibodies. We selected three clones based on biophysical properties, reactivity to HER2 + cancer cells, epitope reactivity and Fc-mediated anti-tumor profiles in vitro. Clones with cross-reactivity to rat HER2 were selected to allow functional evaluations in a fully immunocompetent syngeneic HER2 + rat breast cancer model.RESULTS: IgE antibodies induced degranulation and antibody-dependent cellular cytotoxicity against human and rat HER2-expressing tumor cells in vitro. IgE antibody 26 demonstrated anti-tumor activity in a syngeneic HER2 + rat model, and a human HER2 + breast cancer xenograft model in mice reconstituted with human immune cells. Treatment was associated with enhanced immune cell infiltration and pro-inflammatory immune signatures, and downregulated cancer progression signaling pathways, in the tumor microenvironment.CONCLUSIONS: This study pioneers the design and generation of anti-HER2 IgE lead antibody candidates with immune-stimulating and tumor-restricting effects. The present work may pave the way for antibody engineering therapeutic opportunities for challenging-to-treat HER2-expressing cancers.
AB - BACKGROUND: Tumor-targeting IgE antibodies have elicited potent tumor-restricting effects by recruiting immune effector mechanisms. However, a dedicated platform for the generation, selection and evaluation of novel IgEs based on target antigen recognition and functional profiles has not been reported.METHODS: By establishing an IgE class antibody therapeutic design platform to allow selection of lead candidates, we generated a panel of IgEs recognising the human epidermal growth factor receptor 2 (HER2), overexpressed in 15-20% of breast cancers. From 1840 phage display-generated variable region sequences panned against HER2, we engineered 30 full length IgE antibodies. We selected three clones based on biophysical properties, reactivity to HER2 + cancer cells, epitope reactivity and Fc-mediated anti-tumor profiles in vitro. Clones with cross-reactivity to rat HER2 were selected to allow functional evaluations in a fully immunocompetent syngeneic HER2 + rat breast cancer model.RESULTS: IgE antibodies induced degranulation and antibody-dependent cellular cytotoxicity against human and rat HER2-expressing tumor cells in vitro. IgE antibody 26 demonstrated anti-tumor activity in a syngeneic HER2 + rat model, and a human HER2 + breast cancer xenograft model in mice reconstituted with human immune cells. Treatment was associated with enhanced immune cell infiltration and pro-inflammatory immune signatures, and downregulated cancer progression signaling pathways, in the tumor microenvironment.CONCLUSIONS: This study pioneers the design and generation of anti-HER2 IgE lead antibody candidates with immune-stimulating and tumor-restricting effects. The present work may pave the way for antibody engineering therapeutic opportunities for challenging-to-treat HER2-expressing cancers.
KW - Animals
KW - Humans
KW - Female
KW - Receptor, ErbB-2/immunology
KW - Mice
KW - Breast Neoplasms/immunology
KW - Immunoglobulin E/immunology
KW - Rats
KW - Cell Line, Tumor
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85218463489&partnerID=8YFLogxK
U2 - 10.1186/s13046-025-03319-5
DO - 10.1186/s13046-025-03319-5
M3 - Article
C2 - 39934835
SN - 1756-9966
VL - 44
SP - 49
JO - Journal Of Experimental & Clinical Cancer Research
JF - Journal Of Experimental & Clinical Cancer Research
IS - 1
M1 - 49
ER -