Hyperimmune caprine serum against HIV

Hyperimmune caprine serum against HIV-lysate (AIMSPRO®),
a TNF-α suppressing agent, may modify clinical and respiratory function in ALS
Bryan D. Youl1, Roderick A. Mackenzie2, Simon R. Bailey3
1 The Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom
2 The Prince of Wales Hospital, Randwick, New South Wales 2031, Australia
3 Faculty of Veterinary Science, University of Melbourne, Parkville, Victoria 3010, Australia
N.B. BDY is a director of Daval International Limited, the UK company developing AIMSPRO, and is a stockholder in this company.
Background
FIGURE 2
Hyperimmune caprine serum against human immunodeficiency virus (HIV) lysate
(AIMSPRO) is currently under Phase II trialing in systemic sclerosis (scleroderma)
and secondary progressive multiple sclerosis. Orphan drug designations have been
awarded by the Food and Drug Administration (FDA) in the United States and the
Therapeutic Goods Administration (TGA) in Australia for the use of AIMSPRO in
the treatment of amyotrophic lateral sclerosis (ALS). A small number of ALS
patients have been treated and preliminary open label data suggest that the rate
of decline of respiratory function may be reduced in this condition by its daily
subcutaneous administration. The mechanism of action of AIMSPRO has been
investigated and some findings are presented here.
Case report
FIGURE 3
Subject:
Red:
Green:
Blue:
RM (ALS) 22/3/2005
Pre-treatment
15minutes post AIMSPRO
1 hour post AIMSPRO
Peak response
(% max)
Threshold reduction %
One of the authors (RM) developed asymmetric limb onset sporadic ALS in 2001
and later began treatment with AIMSPRO by sub-cutaneous injection, initially 4.5
mg total protein 2nd daily (AIMSPRO 2nd D) and then daily (AIMSPRO D). He
monitored ALS functional rating scale (ALSFRS-R) every 3 months (Figure 1). The
rating declined by 1.14 each 3 months over 3 years of observation pre-AIMSPRO
and then by 0.03 each 3 months over 51/2 years of AIMSPRO treatment (p<0.001).
He monitored respiratory function tests (RFT) monthly. Before treatment, all RFTs
showed declines consistent with ALS. AIMSPRO therapy improved forced vital
capacity, from a 6 month mean low of 71% to a 6 month average of 92%
predicted at the end of the study (p<0.0001); maximal inspiratory mouth pressure,
from 87% to 99% predicted (p<0.001); and sniff nasal inspiratory pressure, from
72% to 107% predicted (p<0.001). Maximal expiratory mouth pressure remained
around 55% predicted, without significant change.
In addition, electrotonus / threshold tracking recordings were carried out on
motor axons of RM before, and 15 minutes and 1 hour after the administration
of AIMSPRO.
Current (%threshold)
Strength-duration time constant (ms)
FIGURE 1
ALSFRS-R change
50
ALSFRS-R
45
Pre-Aims pro
40
Threshold reduction %
55
Aimspro 2nd D
Aimspro D
LBF
35
30
Delay (ms)
Interstimulus interval (ms)
25
04/2001
09/2002
01/2004
05/2005
10/2006
02/2008
07/2009
11/2010
Graph of amyotrophic lateral sclerosis functional rating scale-revised score
(ALSFRS-R) change from onset, through a 3 year observation period and 51/2
years of treatment. Lines of best fit (LBF) show the average 3 month decline was
1.14 during the observation period, and 0.03 during treatment.
Discussion
To evaluate possible mechanisms of action of AIMSPRO in ALS.
The animal experiments provide evidence that AIMSPRO has anti-inflammatory
activity. The possible importance of TNF-α in the process of neuronal destruction
in ALS means that, if these findings apply to humans, AIMSPRO may moderate this
process. The normalization of SDTC in the same ALS patient raises the possibility
that AIMSPRO can also modify voltage gated ion channel function. This may have
a moderating effect on neuronal hyperactivity in ALS, and may have further
contributed to the improvement shown.
Methods
Conclusions
High and low dose lipopolysaccharide (LPS) controlled experiments were carried
out in mice (Martin and MacIntosh, 2010) and horses (SB)).
AIMSPRO exhibited anti-inflammatory activity in murine and equine endotoxic
models and moderated voltage gated ion channel function of motor axons in an
ALS patient. These effects may explain uncontrolled observations suggesting a
Objectives
Results
In murine and equine LPS models of inflammation, AIMSPRO rapidly produced a
Th-1 to Th-2 shift, with suppression of TNF-α production. The equine study (figure
2) showed a significantly decreased production of TNF-α in animals treated with
AIMSPRO (known as Ceremben in its veterinary form) compared with those
treated with saline. There was also an associated reduction of NFKB production.
Prior to treatment, RM showed an abnormally long strength duration time
constant (SDTC). This was rapidly normalized by AIMSPRO (figure 3, top right
hand graph).
potential benefit of AIMSPRO in ALS. The apparent clinical response in this patient
would have implications for ALS symptom palliation and longevity if replicated in
a multi-centre, double-blind clinical trial using daily AIMSPRO in patients with
advanced ALS. Such a study, with FVC as the primary outcome, is in preparation.
References
Mackenzie R, Kiernan M, Mackenzie D, Youl BD. Hyperimmune goat serum for amyotrophic lateral
sclerosis. Journal of Clinical Neuroscience 2006; 13:1037
Martin C, McIntosh DP (2010). Hyperimmune caprine serum against HIV lysate (AIMSPRO®) shows
protective effect following fatal-dose LPS regimen in mice. (Submitted for publication).