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. First in human clinical trials of AT-1501 began in 2018.
Participants Now Enrolling in Phase 1 Study on AT-1501, a Potential Treatment for ALS
The development of AT-1501, a novel antibody which acts in a highly targeted, disease specific way to tamp down the
immune system. 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.
Anelixis Therapeutics will advance AT-1501 into clinical trials in 2018; an effort that is being supported by some
of the most experienced neurologists in the field. Information about the timing and design of those trials will be
announced by Anelixis as well as ALS TDI.
ALS TDI has received generous charitable support from tens of thousands of individuals over the years,
which has been the primary source of support for the research behind the early discoveries and
development of AT-1501. Additional funding has come from Augie's Quest, ALS Association, ALS Finding a Cure,
ALS ONE and the Department of Defense CDRMP, among others. To donate in support of the discovery and development
of effective treatments for ALS, click here.
Kaplan-Meier time-to-event analysis for
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
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.
Thanks in large part to the generosity of ALS TDI donors, first in human clinical trials of AT-1501 will start
in 2018. However, more than $20 million is likely to be needed to get through dose ranging and other studies in
people with ALS. Anelixis Therapeutics was created by ALS TDI to raise the funding needed to bring AT-1501 through
these crucial clinical trials and will explore other revenue generating opportunities specifically for the advancement
of AT-1501. However, at this time, ALS TDI remains the majority shareholder of Anelixis Therapeutics.
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).
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.
Drugable pathway present in 3 diseased tissues in the SOD1 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.
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.
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