Combining immunotherapeutic antibodies for treatment of cancer patients has shown benefits over single agent treatment. For example, the addition of anti-PD-1 antibodies to anti-CTLA-4 treatment in advanced melanoma patients has increased objective response rates from 19% to 57.6% (Larkin,J et al. 2015. NEJM 373:23-34). 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, particularly through persistent strong expression in a percentage of regulatory T cells (Tregs). 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 LAG-3 and PD-1 leads to T cell exhaustion, allowing tumour escape from immune surveillance. Combining inhibitory antibodies to PD-1 and LAG-3 reactivates T cells leading to efficacy in murine models over single treatment (Woo,S-R et al. 2012. Cancer Res. 15: 917-27) which prompted interest in the development of a LAG-3 and PD-L1 bispecific antibody for inhibiting tumour growth.
A murine-specific anti-LAG-3 and PD-L1 mAb²TM (bispecific antibody) was engineered which binds both antigens 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 an in vitro assay. This potency translates into in vivo efficacy, where the anti-LAG-3/PD-L1 mAb² decreased tumour burden in the MC38 colon carcinoma tumour model, both in early-established or well-established tumours. 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 LAG-3/PD-L1 mAb² showed an increase of anti-tumour activity as compared to the combination of anti-LAG-3 and anti-PD-L1 antibodies. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.
This abstract is also being presented as Poster A27.
Citation Format: Katy Everett, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody. A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR06.