(Asylia) The HSP70 immune axis (HSPA1A, 1B and 1L) is a novel target for cancer immunotherapy – Development and selection of an Fc-enhanced anti-HSP70 IgG for the treatment of pre-clinical models of cancer

Abstract

HSPA1A, -1B, and -1L (HSP70) are unique members of the HSP70 family, situated within the MHC-III genomic locus. These genes play a critical role in the innate and adaptive immune response. Many cancer types overexpress HSP70, leading to enhanced metastasis, protection from apoptosis, and secretion of HSP70. ADP-bound HSP70 is structurally distinct from ATP-HSP70. In the ADP-bound form it carries along with it tumor-derived proteins containing the repertoire of tumor neoantigens. Once processed by an APC, these antigens can be cross-presented via MHC-I or MHC-II complexes to elicit T-cell responses. Attempts for ADP-HSP70-based vaccines in clinical trials lacked robust clinical responses because of limited methods to purify material and successfully target APCs. Here, we report on the development of ASY-77A, a novel anti-HSP70 hu-IgG1 selectively recognizing the ADP-HSP70 neoantigen complex. The engineered Fc domain then redirects these complexes to the activating FcγRs on dendritic cells and macrophages in pre-clinical cancer models.