Anti-CD73(NT5E) Antibodies Specific To The Tumor Microenvironment

SUMMARY

• CD73 is an ectonucleotidase tethered by a glycosylphosphatidyl anchor to the extracellular side of many cell types. Along with NTPDase-1 CD39, CD73 is an important regulator of a cells inflammatory response. Cell death/stress triggers release of ATP which activates pro-inflammatory and immunostimulatory cell pathways. ATP concentrations are decreased through down-regulation by CD39 mediated hydrolysis into ADP and AMP. The CD73 dephosphorylates AMP to adenosine which stimulates anti-inflammatory and immunosupressive responses.
• Many cancerous tissues (e.g., breast, pancreas, prostate bladder) highly overexpress CD73, with an ATP rich tumor microenvironment (TME) possibly resulting in accumulation of CD73. CD73 inhibition has been shown to reduce primary tumor growth and metastasis in mice, and CD73 targeted blocking by AMPCP inhibitors and anti-CD73 mAbs has been shown to reduce tumor growth in vivo. As a result, anti-CD73 therapies have received significant research interest with various antibody clinical trials underway.
• Current clinical trial evaluations of anti-CD73 antibodies do not specifically address the TME. The faculty inventor has developed antibodies whcih exhibit improved biochemcial properties in the presence of high nucleotide concentrations typical of local tumor environments. By specifically targeting the nucleotide-rich TME, the developed antibodies are less likely to result in CD73 inhibition in healthy tissue/cells where CD73 action is important in reducing normal inflammatory response.

FIGURE

ADVANTAGES

ADVANTAGES

• Developed Antibodies Exhibit Improved Binding and Inhibition to Cell Surface CD73 in a TME

•  Enhanced Tumor-Specificity as Compared to traditional/available Anti-CD73 Antibodies

APPLICATIONS

• Oncology
• Immunotherapy
• Drug development

May 8, 2023

Proof of concept

Patent Pending

Licensing,Co-development

Anthony Kossiakoff

• Evaluations were performed on developed antigen-binding fragments (Fab) which indicated they can block CD73 activity by monovalent interaction without oligomerization. Since no hook effect was indicated at higher Fab concentrations, the treatment window of these substances can be enhanced compared to available antibodies. In addition, combining a high nucleotide level and overexpression of CD73 allows concentration of the antibody at the identified tumor location, improving therapeutic value.