Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity.
Resumen: Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies
(mAbs) has shown anti-tumor activity in human trials, but can be associated
with significant off-tumor toxicities involving FcgR interactions. Here, we
introduce albumin-fused mouse and human bispecific antibodies with clinically
favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor
microenvironment. These Fc-free 4-1BB agonists consist of an EGFR-specific
VHH antibody, a 4-1BB-specific scFv, and a human albumin sequence engineered
for high FcRn binding connected in tandem (LiTCo-Albu). We demonstrate
in vitro cognate target engagement, EGFR-specific costimulatory activity, and
FcRn-driven cellular recycling similar to non-fused FcRn high-binding albumin.
The mouse LiTCo-Albu exhibited a prolonged circulatory half-life and in vivo tumor
inhibition,with no indication of 4-1BBmAb-associated toxicity. Furthermore,
we show a greater therapeutic effect when used in combination with PD-1-blocking
mAbs. These findings demonstrate the feasibility of tumor-specific LiTCo-
Albu antibodies for safe and effective costimulatory strategies in cancer
immunotherapy.
Identificador universal: https://hdl.handle.net/10641/3333
Fecha: 2022
Ficheros en el ítem
Ficheros | Tamaño | Formato | Ver |
---|---|---|---|
1-s2.0-S2589004222012305-main.pdf | 2.385Mb | Ver/ |
Este ítem aparece en la(s) siguiente(s) colección(ones)
- MEDICINA [818]