Author: Weber, Daniel P ; Campbell, Phillip L ; Tsou, Pei-Suen ; Gedert, Rosemary J ; Keshamouni, Venkateshwar G ; Wu, Qi ; Lanigan, Thomas M ; Amin, M Asif ; Athukorala, Kalana S ; Singer, Nora G ; Ruth, Jeffrey H ; Lind, Matthew E ; Mao-Draayer, Yang ; Fox, David A ; Lin, Feng ; Gurrea-Rubio, Mikel ; Rasmussen, Stephanie M ; Randon, Peggy M

Limitations of checkpoint inhibitor cancer immunotherapy include induction of autoimmune syndromes and resistance of many cancers. Since CD318, a novel CD6 ligand, is associated with the aggressiveness and metastatic potential of human cancers, we tested the effect of an anti-CD6 monoclonal antibody, UMCD6, on killing of cancer cells by human lymphocytes. UMCD6 augmented killing of breast, lung, and prostate cancer cells through direct effects on both CD8+ T cells and NK cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xenotransplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and downregulated expression of the inhibitory receptor NKG2A on both NK cells and CD8+ T cells, with concurrent increases in perforin and granzyme B production. The combined capability of an anti-CD6 monoclonal antibody to control autoimmunity through effects on CD4+ lymphocyte differentiation while enhancing killing of cancer cells through distinct effects on CD8+ and NK cells opens a potential new approach to cancer immunotherapy that would suppress rather than instigate autoimmunity.

01 Jan 1993·International ImmunologyQ3 · MEDICINE

Activation of human T cells through CD6: functional effects of a novel anti-CD6 monoclonal antibody and definition of four epitopes of the CD6 glycoprotein

Q3 · MEDICINE

Article

Author: Fox, David A. ; Bott, Cynthia M. ; Doshi, James B. ; Morimoto, Chikao ; Romain, Paul L.

The CD6 glycoprotein is expressed primarily on lymphocytes and conveys co-activating signals to T cells, but its exact function and ligand(s) are unknown. A novel mAb, termed UMCD6, was demonstrated to recognize CD6 by immunoprecipitation, Western blotting, and reactivity with COS cells transfected with CD6 cDNA. UMCD6 was mitogenic for T cells and was strongly synergistic with phorbol ester in inducing T cell activation. UMCD6 enhanced the autologous mixed lymphocyte reaction as previously observed with another anti-CD6 mAb, anti-T12. The activating effects of UMCD6 were more striking than those of other anti-CD6 mAbs and encompassed all of the diverse stimulatory properties previously reported for other anti-CD6 reagents. However, neither UMCD6 nor other anti-CD6 antibodies alone or in combination with phorbol ester or IL-2 were able to induce thymocytes to proliferate. Stimulation by UMCD6 is dependent on accessory cell function in a manner not accounted for simply by antibody cross-linking. UMCD6 did not induce an increase in cytoplasmic free Ca2+, but the CD6 activation pathway appears to involve protein kinase C. UMCD6 and a panel of seven other anti-CD6 mAbs were used in a series of experiments to define four discrete epitopes of CD6 using the criteria of antibody cross-blocking, reactivity on reduced Western blots, and resistance to controlled V8 protease digestion. The functional mAbs UMCD6, 2H1, and anti-T12 each recognized a different epitope. Taken together, the results of these studies strongly reinforce the hypothesis that CD6 plays a significant and distinct role in T cell activation, and suggest that multiple regions of CD6 may be functionally active.

Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells

Author: Wu, Qi ; Amarista, Camila E ; Gurrea-Rubio, Mikel ; Mao-Draayer, Yang ; Ikari, Yuzo ; Ding, Shengli ; Shen, Xiling ; Lind, Matthew E ; Fox, David A ; Lin, Feng ; Mattichak, Megan N ; Ruth, Jeffrey H ; Tsou, Pei-Suen ; Muraoka, Sei ; Campbell, Phillip L ; Amin, M Asif ; Cooney, Laura A ; Brodie, William D ; Randon, Peggy M

AbstractImmune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8+ T cells. Tumor-infiltrating cytotoxic lymphocytes were found in higher proportions and were activated in UMCD6-treated mice compared to controls. Similar changes in gene expression were observed by RNA-seq analysis of NK cells treated with UMCD6. Particularly, UMCD6 up-regulated the NKG2D-DAP10 complex and activated PI3K. Thus, the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	The University of Michigan-Dearborn	-
Lung Cancer	Preclinical	US	The University of Michigan-Dearborn	-
Prostatic Cancer	Preclinical	US	The University of Michigan-Dearborn	-

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