CD6 was discovered over 30 years ago as a surface marker of T-cells, an important T-cell costimulatory and adhesion molecule and has been suggested as a target for treating many autoimmune diseases, including autoimmune uveitis, multiple sclerosis (MS), rheumatoid arthritis, and Sjögren's syndrome. It is found almost exclusively on T-cells. In pilot studies, we have developed a novel high-affinity monoclonal antibody (mAb), ATX006, against human CD6 and demonstrated that this mAb is highly effective in suppressing autoreactive T cell responses that lead to tissue damage in several models of autoimmune diseases. By conjugating this mAb to a mitotic toxin, MMAE, we have also demonstrated the ability of the antibody-drug conjugate (ADC), ATX101, to target the killing of dividing T-cells, which are common in most T-cell lymphomas, while sparing normal T-cells. Although this antibody inhibits the development of autoimmunity, it also stimulates lymphocytes to more efficiently attack and kill cancer cells.
ATX101 As A Treatment For T-Cell Lymphoma (TCL)
ATX101 represents a novel strategy for the treatment of TCL. This antibody-drug conjugate targets the CD6 cell surface protein found on T-cells. Studies using ATX101 have demonstrated its selective binding to T-cells and, through its anti-mitotic payload, ATX101 selectively kills dividing T-cells, such as the T lymphoma cells and autoreactive T cells, while sparing the non-dividing “normal” T-cells despite their expression of CD6. CD6 has been found in almost all patient TCL biopsies analyzed to date. In animal models of TCL, treatment with ATX101 not only leads to shrinkage in tumor size, but also inhibits tumor metastasis. ATX101 is effective not only in models of peripheral TCL but also in models of cutaneous TCL. Abcon is now partnering with the NCI’s NExT program to manufacture ATX101 and demonstrate its safety in preclinical IND enabling toxicology studies, prior to initiating human clinical trials.
ATX006 Role in Treating Cancer
ATX006 is a high affinity, anti-CD6 mAb that rapidly caps and internalizes CD6 and therefore does not deplete lymphocytes by complement fixation or Fc receptor engagement and is unlikely to impair host defenses against infection. This mAb directly activates lymphocytes that kill cancer cells, even in the absence of CD4+ T cells. Unlike the checkpoint inhibitors, ATX006 should suppress rather than induce autoimmunity in cancer patients, thus creating the potential for safe, long-term administration leading to favorable clinical outcomes in a much higher proportion of cancer patients compared to results seen with currently used cancer immunotherapies. CD6-/- mice are healthy and are protected from induction of autoimmune models of multiple human diseases. In contrast, genetic deficiency in mice or humans of PD-1, PD-L1 or CTLA4 leads to spontaneous occurrence of widespread, fatal autoimmune inflammation. ATX006 has been shown to shrink tumors in models of triple negative breast cancer, prostate cancer and non-small cell lung carcinoma.
ATX101 and ATX006 in the Treatment of Autoimmune Diseases
T-cells play a major role in autoimmunity and their abnormal proliferation can lead to a multitude of problems. For example, autoimmune uveitis is a major cause of blindness in which proliferating retinal antigen-specific T-cells lead to ocular inflammation and vision loss. Since these T-cells express CD6, we tested the ability of the mouse anti-CD6 ADC, a precursor to ATX101, to treat problems in an experimental automimmune uveitis model. In this model, mice treated with a control antibody or with our anti-CD6 mAb, showed significant inflammation in the eye with infiltrating cells, papilledema, and large lesions, which led to retinal damage. Treatment with the anti-CD6-ADC significantly protected the mice from inflammation and retinal damage. A single dose of the anti-CD6 ADC was also effective at eliminating pathogenic T-cells in an animal model of graft-versus-host disease.
In addition, treatment with our anti-CD6 monoclonal antibody, ATX006, has led to outstanding results in multiple mouse models of human autoimmune disease, including rheumatoid arthritis, multiple sclerosis and uveitis.