Fully Human Anti-cluster of Differentiation-22 (CD22) Engineered Antibody VH Domains

Researchers at Pitt have developed fully human anti-cluster of differentiation-22 (CD22) engineered antibody VH domains as potential therapeutic targets for treating B cell malignancies and other lymphoid cancers.

Description

CD22 is a 135 kDa transmembrane protein expressed uniquely on the surface of B lymphocytes, with higher concentrations on mature B cells than precursor B cells. CD22 functions as an inhibitory receptor for B cell receptor (BCR) signaling, preventing the over-activation of the immune system and the development of autoimmune diseases. B cell malignancies have become the fourth leading subtype of cancer, with over 130,000 new estimated cases annually in the United States.

Applications

- B cell malignancy therapeutics
- Lymphoid cancer therapeutics

Advantages

While anti-CD20 therapies (rituximab and obinutuzumab) and anti-CD19 therapies (blinatumomab) have significantly improved outcomes in lymphoid malignancies, there are limited therapeutic options for patients who progress after these treatments, making CD22 an attractive target for therapy development. Monoclonal antibody (mAb) based therapeutics targeting CD22 have shown substantial clinical success, with two anti-CD22 antibody drug conjugations (Besponsa and Lumoxiti) approved by the U.S. Food and Drug Administration (FDA). Several anti-CD22 CAR-T/NK based therapies are also currently under clinical trials. The novel and unusual features of these fully human anti-CD22 antibody domains include their smaller size, which may enhance penetration and access to some hidden epitopes, and their improved aggregation resistance. Additionally, the ability to target different epitopes on CD22 makes it feasible to construct paratopic antibodies. These human-derived antibody domains are expected to have less immunogenicity and could be more flexible in the application of CD22-targeting CAR-T/NK cell therapies, as well as other therapies including bispecific antibody-drug conjugates, immunotoxins, and paratopic antibody-drug conjugates.

Invention Readiness

This technology is at the level of in vitro data. The researchers have generated a large human antibody VH domain phage-displayed library and identified a panel of 3 fully human single VH domains from this library that are specific for human CD22. These antibody domains have molecular weights around 15 kDa, much smaller than full-length IgG (~150 kDa). All three antibody domains showed EC50 ranging from 0.4 - 50 nM in binding to recombinant human CD22, and they exhibited potent binding activities to B cells but no binding to T cells. Competition ELISA showed that they target different epitopes on human recombinant CD22.

IP Status

Patent Pending

Related Publication(s)

Sun, Z., Li, W., Mellors, J. W., Orentas, R., & Dimitrov, D. S. (2022). Construction of a Large Size Human Immunoglobulin Heavy Chain Variable (VH) Domain Library, Isolation and Characterization of Novel Human Antibody VH Domains Targeting PD-L1 and CD22. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.869825