A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models
Matthew Kraman, Katarzyna Kmiecik, Carlo Zimarino, Katy Everett, Barbara Hebeis*, Mustapha Faroudi, Mateusz Wydro, Jacqueline Doody
F-star, Cambridge, UK
Combining immunotherapeutic antibodies in cancer treatment has shown benefits over single agents. An alternative to combining two antibodies is the development of bispecific antibodies that not only bring two biologies together but may result in novel mechanisms of action that are impossible to attain with combinations.
Lymphocyte Activation Gene-3 (LAG-3) is a member of the Ig superfamily expressed on activated T cells, NK cells, pDCs, B cells, γδ T cells and participates in immune suppression. Programmed Cell Death receptor (PD-1) binds to its ligand PD-L1, expressed not only on activated immune cells to inhibit cellular immune responses but also on tumour cells. Expression of both these surface molecules therefore leads to T cell exhaustion allowing the tumour to escape immune surveillance.
A mAb² TM (bispecific antibody) was engineered which binds murine LAG-3 and PD-L1 simultaneously and with nanomolar affinities. The anti-LAG-3/PD-L1 mAb² inhibits LAG-3 binding to MHCII and PD-L1 binding to PD-1 and CD80, resulting in T cell activation in vitro. This translates into in vivo efficacy, where the mAb² decreased tumour burden in the MC38 colon carcinoma tumour model. At the end of the study tumour-free animals were more numerous in the LAG-3/PD-L1 bispecific group than in the group given a combination of individual anti-LAG-3 and PD-L1 antibodies. The results were recapitulated in the CT26 murine colon cancer model, where the mAb² showed an increase of anti-tumour activity as compared to the antibodies given in combination. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.