Discovery and Characterization of Two anti-PD-1 Antibodies with a Unique Binding Mechanism to human PD-1

Authors

Keyla María Gómez Castellano^a,b, Alejandra Montes Luna^a,b, Gregorio de Jesús Carballo Uicab^a,b, Frida Daniela Ramírez Villedas^a,b, Luis Javier Elizarrarás Rodríguez ^a,b, Said Kayum Vázquez Leyva^a,b, Stefany Daniela Rodríguez Luna^a,b, Edith González González^a,b, María Martha Pedraza Escalona^c, Ben Holland^d, Pietro Della Cristina^d,e, Carolina Rivera Santiago^f, Hugo Alberto Barrera Saldaña^f, Sonia Mayra Pérez Tapia^a,b,g, and Juan Carlos Almagro^a,h

Organizations

a. Unidad de Desarrollo e Investigación en Bioterapéuticos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto PolitécnicoNacional, Miguel Hidalgo, México
b. Laboratorio Nacional Para Servicios Especializados de Investigación, Desarrollo e Innovación(I + D + I) Para Farmoquímicos y Biotecnológicos, LANSEIDI-Farbiotec-CONACyT, Miguel Hidalgo, México
c. SECIHTI-UDIBI,Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Miguel Hidalgo, México
d. Antiverse Ltd., Cardiff, UK
e. AstraZeneca, Biologics Engineering, Cambridge, UK
f. Dirección de Investigación Científica Básica, Laboratorios Columbia SA deCV, Coyoacán, Mexico
g. Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional,Miguel Hidalgo, México
h. GlobalBio, Inc., Cambridge, MA, USA

Abstract

Targeting checkpoint inhibitors is an effective therapy for treating cancer, with human programmed cell death protein 1 (hPD-1) being one of the most successful targets for developing antibody-based drugs. In this work, we isolated a panel of anti-PD-1 single-chain variable fragments with different binding and functional profiles from a fully synthetic human phage display library. Conversion of the best clone to hIgG1LALA and hIgG4PE formats, called UDIZ-007 and UDIZ-008, respectively, resulted in antibodies that effectively blocked the PD-1:PD-L1/L2 interaction and were highly selective as they did not cross-react with CD28 receptor family members. Doses of UDIZ-007 or UDIZ-008 at 10 mg/kg every 3 days for a total of six intraperitoneal administrations eradicated MC38-hPD-L1 colon tumors in B-hPD-1 transgenic mice for hPD-1 at day 17, with no relapse until the end of the study at day 56. Importantly, these antibodies bind hPD-1 in a unique region compared to the anti-PD-1 antibodies of known structure, which might have an impact on novel oncology indications when used as a standalone therapy or in combination with currently approved anti-PD-1 therapeutic antibodies. Therefore, UDIZ-007 and UDIZ-008 seem to be promising candidates for the development of antibody-based drugs targeting checkpoint inhibitors as a treatment for cancer.

CovalX Technology Used

Epitope Mapping