Public Teleconference Regarding Licensing and Collaborative Research Opportunities for: A Promising Treatment for Inflammatory Arthritis Targeting the Pre-ligand Assembly Domain (PLAD) of Tumor Necrosis Factor Receptors; Michael J. Lenardo et al. (NIAID), 59801 [E6-16735]

Agencies

• DEPARTMENT OF HEALTH AND HUMAN SERVICES
• National Institutes of Health

[Federal Register Volume 71, Number 196 (Wednesday, October 11, 2006)]
[Notices]
[Page 59801]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-16735]



[[Page 59801]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

[HHS Reference Nos. E-095-2000/0, 1, 2, 3 and 4]


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: A Promising Treatment for Inflammatory 
Arthritis Targeting the Pre-ligand Assembly Domain (PLAD) of Tumor 
Necrosis Factor Receptors; Michael J. Lenardo et al. (NIAID)

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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Technology Summary

    The technology is an innovative treatment for inflammatory 
arthritis that involves modulating Tumor Necrosis Factor Receptor 
(TNFR) 1 signaling. NIH scientists have discovered that the Pre-ligand 
Assembly Domains (PLADs) of TNFR1 can be selectively blocked by soluble 
P60-PLAD protein compositions (P60 PLAD-Sol) which interfere with TNFR1 
assembly thereby preventing the inflammatory effects of TNF[alpha] both 
in vitro and in vivo.

Technology Description

    Current anti-TNF[alpha] arthritis treatments rely on the use of 
antibodies or fusion proteins directed against TNF[alpha] to reduce 
inflammation. The cytokine TNF[alpha] plays a key role in the 
pathogenesis of numerous autoimmune and inflammatory diseases including 
psoriatic, rheumatoid, and septic arthritis. It has been shown that 
blocking TNF[alpha] has a dramatic therapeutic effect; however, 
blocking TNF[alpha] also blocks TNF[alpha]'s beneficial effects during 
immune responses that are mediated through TNFR2.
    This invention involves a functional domain, which is essential for 
signaling involving receptors of the TNFR superfamily including TNFR-1 
(p60), TNFR-2 (p80), FAS, TRAIL-R, LTR, CD40, CD30, CD27, HVEM, OX40 
and DR4. PLADs can be isolated as functional polypeptides which can be 
useful in inhibiting the first step in TNFR mediated signaling, ligand-
independent assembly of members of the TNFR superfamily. The ability to 
inhibit TNFR signaling suggests that these PLAD polypeptides may be 
useful in developing new therapeutic molecules or as therapeutic 
molecules themselves.
    P60 PLAD-Sol has the benefit of selectively blocking only the 
signaling of TNFR1, not signaling mediated through TNFR2. Treatment of 
mice with the P60 PLAD-Sol ameliorated inflammatory joint disease with 
no side effects in 5 different animal models of arthritis including: 
collagen-induced arthritis, adjuvant and lipopolysaccharide induced 
arthritis, and joint disease due to TNF. Therefore, P60 PLAD-Sol may 
lead to novel inflammatory arthritis treatments that avoid the serious 
side effects associated with currently marketed therapeutics that 
directly block TNF[alpha] rather than TNFR1.

Competitive Advantage of Our Technology

    More than 20% of the population in the USA currently seek arthritis 
treatment; of these over 2 million suffer rheumatic symptoms. Worldwide 
this figure is close to five million people. Existing commercially 
available anti-TNF[alpha] treatments are expensive: in the U.S. 
Enbrel[reg], Remicade[reg], and Humira[reg] all cost more than $10,000 
per year. In addition to this market there is the potential to treat 
other inflammatory based diseases such as Crohn's Disease and Multiple 
Sclerosis. Owing to the high price of these agents and their increased 
use in treatment, the market for TNF[alpha] inhibitors is expected to 
grow from $7.1 billion in 2005 to nearly $12 billion in 2014 in the 
United States, Western Europe, and Japan.
    The existing TNF blockers, e.g., Enbrel[reg] (Etanercept--a dimeric 
fusion protein by Amgen/Wyeth), Remicade[reg] (Infliximab--a mouse 
chimeric anti-TNF monoclonal antibody by J&J), and Humira[reg] 
(Adalimumab--a humanized anti-TNF monoclonal antibody by Abbott) have 
been effective in the treatment of rheumatoid arthritis. They are 
beneficial in over 70% of patients including many who have not 
responded to Rheumatrex[reg] (Methotrexate--an antimetabolite by 
STADA); however, serious and sometimes fatal side effects have been 
observed. In addition, the current costs of these drugs are prohibitive 
for many patients. This technology has the potential to be less 
expensive yet more effective than existing products.
    For arthritis sufferers who are unresponsive to, or adversely 
affected by, current inflammatory arthritis treatments our technology 
is a new method of blocking inflammation that provides a more targeted 
action. Unlike the currently marketed anti-TNF medications, P60 PLAD-
Sol has the potential to more effectively treat a broader range of 
inflammatory diseases with no known side-effects. The current anti-TNF 
drugs directly block the binding of TNF[alpha] to both TNFR1 and TNFR2. 
There is evidence that this inhibits the beneficial effects mediated by 
TNFR2, while arresting the disease-causing effects of TNFR1. This is 
because the P60 PLAD-Sol involves the use of small soluble proteins 
that preferentially target only the PLAD of TNFR1. In our models, a 
dose of a P60 PLAD-Sol (5 mg/kg) had similar effects to doses of 
Infliximab (10 mg/kg) and Etanercept (0.4 mg/kg) that have been used 
clinically in the amelioration of arthritis. As a selective TNFR1 
blocking agent, this technology may avoid the serious side effects of 
these currently available compounds yet have enhanced efficacy.

Patent Estate

    A PCT application, filed 9 February 2001 (WO 01/58953), has entered 
the national phase in the US, EP, AU and CA.

Next Step: Teleconference

    There will be a teleconference where the principal investigator 
will discuss non-confidential information concerning this technology. 
Licensing and collaborative research opportunities will also be 
discussed. If you are interested in participating in this 
teleconference please call or email Mojdeh Bahar; (301) 435-2950; 
baharm@mail.nih.gov. OTT will then e-mail you the date, time and number 
for the teleconference.

    Dated: October 2, 2006.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E6-16735 Filed 10-10-06; 8:45 am]
BILLING CODE 4140-01-P