Data showing successful immune reset with a single dose of CD45-ADC, an antibody-drug conjugate, in models of three autoimmune diseases, were presented at the annual meeting of the American College of Rheumatology (ACR) held November 8 – 13, 2019 in Atlanta, Georgia.

CD45-ADC is an antibody-drug conjugate using an amanitin payload developed by Heidelberg Pharma and targets CD45, a protein expressed exclusively on nearly all blood cells including hematopoietic stem cells (HSCs). The investigational agent is being developed by Magenta Therapeutics.[1]

The researchers conclude that the presented results from preclinical studies suggest that targeted immune depletion with a single treatment of CD45-ADC may be sufficient for auto-HSCT and allow re-establishment of immune tolerance. They also conclude that targeted CD45-ADCs may represent a safer and better tolerated approach for conditioning patients prior to immune reset through autoHSCT and significantly reduce the side effects associated with current conditioning.[1]

Autoimmune disease
“Millions of patients worldwide live with debilitating autoimmune diseases, with no options for curative therapy,” noted John Davis, MD, M.P.H., Chief Medical Officer, Magenta Therapeutics.

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“Magenta is developing targeted medicines such as CD45-ADC to enable more patients with autoimmune diseases to undergo a one-time, curative immune reset. The data presented at ACR provide important proof of concept for our immune reset platform across a broad range of diseases, including multiple sclerosis and systemic sclerosis. We expect to declare a development candidate and progress this medicine into IND-enabling studies next year as we work to allow more patients to live their lives without autoimmune disease,” Davis added.

Multiple Sclerosis Results
Data presented at the annual meeting of the American College of Rheumatology demonstrated that a single dose of CD45-ADC removed disease-causing reactive T-cells, enabled successful immune reset and rebuild of the immune system and was well tolerated in a reliable murine model of autoimmune disease, the EAE model.

The data showed that a single dose of CD45-ADC significantly reduced disease incidence and delayed disease onset in this model that has successfully provided preclinical proof of concept for many clinically validated standard-of-care therapies.

Systemic Sclerosis Results
Data presented at the American College of Rheumatology also showed that a single dose of CD45-ADC eliminated disease-causing effector cells and ameliorated disease in a humanized murine model of systemic sclerosis with skin involvement.

Mice treated with CD45-ADC showed clear resolution of skin lesions and regrowth of hair, while animals treated with an isotype ADC showed no improvement. CD45-ADC was well tolerated.

Inflammatory Arthritis Results
Finally, data presented at the American College of Rheumatology showed that a single dose of CD45-ADC enabled immune reset and rebuild and halted disease progression in a murine model of inflammatory arthritis.

The disease-modifying effects of this well-tolerated one-time approach were equivalent to multiple doses of a neutralizing anti-TNFα antibody, which replicates a clinically validated approach to treatment of rheumatoid arthritis.

Current standards
Current standard treatment for patients with multiple sclerosis involves years of chronic dosing of medications that do not halt the progression of the disease. For patients with systemic sclerosis, a potentially fatal disease, there are no approved therapies.

Immune reset through stem cell transplant has demonstrated durable remissions in thousands of patients with autoimmune diseases such as multiple sclerosis and systemic sclerosis, and it is recommended by the European League Against Rheumatism (EULAR) in treatment guidelines for systemic sclerosis.

The immune reset process involves two main steps:

  • Removing the disease-causing cells and
  • replacing them with healthy cells to rebuild the immune system to a healthy state.

To date, Magenta is the only company developing targeted antibody-drug conjugates designed to precisely remove the disease-causing cells in the body without the need for chemotherapy or radiation.

Magenta’s CD45-ADC program targets CD45, a protein expressed on immune cells and stem cells, and is designed to remove the cells that cause autoimmune diseases to enable curative immune reset.

Collaboration
In March 2018, Heidelberg Pharma and Magenta Therapeutics signed an exclusive multi-target research agreement under which Magenta gained access to Heidelberg’s amanitin toxin-linker platform technology. Based on this agreement, Magenta may apply Heidelberg’s proprietary amanitin technology for up to four exclusive targets to produce novel Antibody Targeted Amanitin Conjugates. Heidelberg is entitled to receive development and sales-related milestone payments totaling $85 million per selected target.

Magenta selected CD117 as its first target and exercised that option in October 2018. Earlier this week the company announced that it has exercised a second option for exclusive worldwide development and marketing rights for antibody-drug conjugates using an amanitin payload and targeting CD45.

Reference
Gillard G, Proctor J, Brooks M, Lamothe T, Hyzy S, McDonough S, Palchaudhuri R, Bhat A, Sarma G, Bhattarai P, Sawant P, Pearse B, McDonagh C, Boitano A, Cooke M. Administration of a CD45 Antibody Drug Conjugate as a Novel, Targeted Approach to Achieve Immune System Reset: A Single Dose of CD45-targeted ADC Safely Conditions for Autologous Transplant and Ameliorates Disease in Multiple Models of Autoimmune Disease [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). Abstract #120. Last accessed November 12, 2019.