An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo

Abstract

Carbonic anhydrase XII (CAXII) is a membrane-tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co-expressed along with the P-glycoprotein (P-GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P-GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P-GP activity in CAXII/P-GP double-positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple-negative breast cancer xenografts co-treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting.

Carbonic anhydrase IX enhances tumor cell proliferation and tumor progression in osteosarcoma

“…A recent study had demonstrated that CA XII inhibitor abrogates chemoresistance and significantly reduces lung metastases in in vivo breast cancer model. 35 A similar CA XII inhibition by 215900 might have contributed to the inhibitory effects observed in this study. Further studies are required to characterize 215900-mediated CA XII inhibition and to elucidate the role of CA XII in human osteosarcoma.…”

Deep learning reveals cancer metastasis and therapeutic antibody targeting in whole body

“…Focusing on a clinically relevant tumor model, we transplanted human MDA-MB-231 mammary carcinoma cells, expressing mCherry and firefly luciferase, into the mammary fat pad of NOD scid gamma (NSG) mice and allowed the tumors to grow and metastasize for 6-10 weeks (Figure 1A) [18][19][20] . Furthermore, we injected the fluorescently-tagged 6A10 therapeutic antibody that has been shown to reduce tumor burden in this model 19,20 . To investigate cancer metastasis and therapeutic antibody targeting in whole mouse bodies at the single cell level, we developed DeepMACT.…”

“…However, so far there has been no methodology to determine the distribution of therapeutic antibodies in the entire body at cellular resolution. Here, we used DeepMACT to assess biodistribution of the therapeutic monoclonal antibody 6A10 directed against human carbonic anhydrase XII (CA12) 19,20,24 . CA12 is overexpressed in various types of cancers and blocking its activity with the antibody 6A10 reduces tumor growth 19 and increases the sensitivity of tumor to chemotherapy 20 .…”

“…Here, we used DeepMACT to assess biodistribution of the therapeutic monoclonal antibody 6A10 directed against human carbonic anhydrase XII (CA12) 19,20,24 . CA12 is overexpressed in various types of cancers and blocking its activity with the antibody 6A10 reduces tumor growth 19 and increases the sensitivity of tumor to chemotherapy 20 . We intravenously injected 20 µg of 6A10 conjugated to Alexa-568 (with tumor signal boosted with Atto-647N) nine weeks after transplantation of MDA-MB-231 cells and perfused the mice two days after the antibody injection for whole-body analysis.…”

Advances in Ex Situ Tissue Optical Clearing

“…Pioneering lung BABB clearing was reported by Scott et al., who presented the first detailed view on the relationship between nerves, vessels and airways architecture, detected novel patterns of pleural innervations and connectivity patterns of pleural nerves. Solvent‐based clearing proved also beneficial for the detection and analysis of lung tumor metastases …”