AT-1501

AT-1501 (antiCD40L) is an antibody therapeutic with comprehensive and promising preclinical data. It blocks specific immune cell activation and protects nerves against the progression of ALS and Alzheimer's Disease.

Is it the real deal?

The development of AT-1501, a novel antibody which acts in a highly targeted, disease specific way to tamp down the immune system, is now ready for clinical translation. Developed at the ALS Therapy Development Institute, this potential therapeutic has been screened in more preclinical efficacy experiments than any other compound proposed in the history of the battle to end ALS. And, working closely with people with ALS in the lab and in the clinic, we have identified candidate biomarkers that will allow us to more rapidly conduct clinical trials. AT-1501 will not make it to the clinic without immediate philanthropic support.

AT-1501 Results

Kaplan-Meier time-to-event analysis for

  • (A) time required to attain peak body weight (p=0.353)
  • (B) time from peak body weight until death (p=0.041)
  • (C) disease onset (neurological severity score of 2) (p=0.004) and
  • (D) survival (p=0.004) by MR1 treatment or vehicle control.

N=18 female and 18 male SODG93A mice receiving MR1 treatment and N= 16 female and 18 male SODG93A mice in the control group. Female mice received a loading dose of 5.22mg/kg MR1 (a form of antiCD40L treatment) at age 50 days and maintenance doses of 0.1mg/kg weekly until death. Male mice received loading doses of 6.75mg/kg and maintenance doses of 0.1mg/kg, according to the same timeline. Results published in Nature Genetics (2010).

Pooled human peripheral blood mononuclear cells (PBMCs) from three healthy controls were activated with PMA/ionomycin. Activated PBMCS were then pre incubated with PBS (negative control), Abetacept (negative control), 5c8 human anti CD40LG (positive control), JB5-D3 anti CD40LG lead candidate, AT-1501 anti CD40LG re cloning of JB5 done at Lonza, Stage 3 material (10L bioreactor of AT-1501 prepared at Lonza, Stage 23 (20L bioreactor of AT-1501 prepared at Lonza for 4 hours. Cells were then treated with 5c8_AF-488 for 4 hours and then FACS sorted. Cell exposed to negative controls showed high levels of fluorescent 5c8-AF-488 binding since they do not block CD40LG on the cell surface of activated PBMCs. All positive controls blocked binding of 5c8_AF-488 to CD40LG on the cell surface demonstrating potent functional activity for AT-1501.

We need you

“AT-1501 is the most effective treatment tested at the ALS Therapy Development Institute!”
Steve Perrin, Ph.D.
CEO/CSO

At this moment, AT-1501, our most promising treatment candidate, is literally sitting in a freezer. Why? Because we need funding to advance AT-1501 out of the freezer and into people living with ALS.

 

Donate

Discovery of the pathway

 

SOD1G93A Tissue Interactome

  • 3 Tissues:
    • muscle
    • spinal cord
    • sciatic nerve
  • 8 time points:
    • days 30, 50 , 60
    • 80, 90, 100, 110, 120
  • 45,000 genes
    • Affy: MOE430vII
  • SOM Clustering of TxP
    • 100 clusters per tissue
  • 498 biological pathways
    • kegg, biocarta
  • 22,830 nodes
  • 52, 857 interactions
  • Statistics
  • Limma package (R)
    • Estimate changes in mRNA
  • GlobalTest (R)
    • Estimate changes in biological pathways based on geometric mean

 

In 2007 The Institute conducted the largest gene expression analysis from multiple tissues in the SOD1G93 mouse model. This interactome depicts the gene expression changes (small yellow nodes at the center of picture) at 8 time points from skeletal muscle, spinal cord, and sciatic nerve and how they overlap across tissues. The network was annotated by mapping the genes onto known biological pathways from the Kegg and Biocarta databases (concentric circles around each tissue).

Statistical Data Mining Identifies
Biologically Relevant Pathways

 

In a 2007 statistical analysis of the large gene expression database from the SOD1G93A mouse model identified hundreds of pathways that are activated in various tissues during disease progression in ALS. Pathways for cellular stress, endoplasmic reticulum stress, mitochondrial dysfunction, synaptogenesis and dozens of others were identified in the spinal cord. Pathways for myoblast activation, neuromuscular junction remodeling, and growth factor activation were identified in skeletal muscle. Pathways for schwann cell dysfunction and remyelination were identified in the sciatic nerve. A common set of immune modulatory pathways commonly known as the costimulatory pathway were up regulated in all three tissues as well as in brain, thymus, and lymph nodes.

CD40LG Pathway is Increased in Multiple Tissues

Spinal Cord

Muscle

Sciatic Nerve

 

  • Longitudinal gene expression changes from the SOD1 mouse model
  • Co-Stimulatory pathway is an immune modulatory pathway
  • Activated in spinal cord, skeletal muscle, sciatic nerve

Drugable pathway present in 3 diseased tissues in the S0D1 pre-clinical model

 

The representation of the Costimulatory Pathway is from Biocarta. Each gene in the pathway is represented by a rectangle. The changes in gene expression in each tissue from SOD1G93A mice compared to wild type littermates are shown for each gene in the costimulatory pathway for spinal cord, skeletal muscle, and sciatic nerve. The rectangle for each gene is divided by hashes to delineate time points from day 50 to day 120. Changes in gene expression at each time point are represented colorimetrically. Pink being up regulated in SOD1G93A mice and Blue being down regulated in SOD1G93A mice.

 

 


 

Mohan, 1995
Shepard, 1999
Laman, 2002
Davidson, 2003
Danese, 2004

 

A schematic of the cell types and receptors in the costimulatory pathway. Two signaling networks control activation of the costimulatory pathway: 1) binding of CD28 on T cells to B7 receptors on macrophages and dendritic cells (also called antigen presenting cells (APCs)), and 2) binding of CD40LG on activated T cells to CD40 on APCs. Such binding induces expression of adhesion molecules and pro-inflammatory signaling molecules on T cells and APCs. A significant body of work has demonstrated the therapeutic potential of blocking CD40LG function and also that it ameliorates disease in preclinical models of tissue transplantation and autoimmunity.