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Thursday, 07/17/2008 9:01:58 AM

Thursday, July 17, 2008 9:01:58 AM

June2007: Peregrine licensed ‘certain Anti-PS antibodies’ from UCLA

Is the inventor of these Dr. Pojen Chen, a CHAVI/HIV researcher (w/Haynes), who was a 12-2007 addition to PPHM’s SRB? Is ‘IS1’, referenced in Haynes’ recently published “Method of Inducing Neutralizing Antibodies to HIV” patent app., among those licensed from UCLA? Do those ‘certain [UCLA] Anti-PS antibodies’ that PPHM now controls include others that Dr. Chen (or others at UCLA) have discovered? Recall, Chen’s 1999 Hematology paper said, “additional ones to be generated.” To what extent does this UCLA-prong of PPHM’s ever-growing Anti-PS platform weave into the Duke/CAVD/CHAVI HIV initiative, vis-à-vis PPHM’s UTSW/Thorpe Anti-PS arsenal? A few facts to ponder while we wait on the Duke papers and revelations (assembled mostly from prev. JBM posts)…

I. On 12-18-07, Dr. Chen was added to the Peregrine website:
PEREGRINE PHARMACEUTICAL'S SCIENTIFIC RESOURCE BOARD (SRB)
CORE TECHNOLOGIES:
Pojen P. Chen, Ph.D. – Professor of Medicine, Dept of Medicine, Rheumatology Division, Univ. of California Los Angeles [UCLA] http://www.peregrineinc.com/index.php?option=com_content&task=view&id=15&Itemid=29
Two BIO pages for Dr. Chen:
http://www.cancer.ucla.edu/index.aspx?page=243&recordid=315
http://dgsom.healthsciences.ucla.edu/institution/personnel?personnel_id=46758
Dr. Chen’s Pub’s: http://tinyurl.com/2evl5k

II. On 7-14-08, Peregrine added this to their 10K, in the “LICENSE, RESEARCH AND DEVELOPMENT AGREEMENTS” section on pg. F-23:
“During June 2007, we entered into an exclusive license agreement with The Regents of the University of California regarding the use of certain Anti-PS antibodies to be used as a possible future generation clinical candidate. Under the terms of the agreement, we paid a non-refundable up-front license fee of $25,000, which is included in research and development expense in fiscal year 2008 in the accompanying consolidated financial statements. In addition, under the terms of the agreement, we are obligated to pay an annual maintenance fee, clinical development milestone fees and a royalty on net sales. Our aggregate future clinical development milestone payments under the license agreement are $735,000 assuming the achievement of all developmental milestones under the agreement through commercialization of the product. We do not anticipate making any milestone payments for at least the next fiscal year under this agreement.”
http://www.sec.gov/Archives/edgar/data/704562/000101968708003034/peregrine_10k-043008.htm

III. Pojen Chen’s Work with Antiphospholipid Syndrome-derived Mabs IS1/2/3/4…
A. British Journal of Haematology - April 1999, 105:1
“Characterization Of Igg Monoclonal Anti-Cardiolipin/Anti-Beta2gp1 Antibodies from Two Patients with Antiphospholipid Syndrome Reveals Three Species of Antibodies”
Zhu, Olee, Le, Roubey, Hahn, Woods, Pojen P. Chen
Division of Rheumatology, Univ. of California Los Angeles [UCLA]
ABSTRACT:
Antiphospholipid antibodies (aPL), including antibodies detected in anti-cardiolipin (aCL) enzyme-linked immunosorbent assays and in lupus anticoagulant (LA) tests… To address the issue of aCL specificity we generated 5 new monoclonal IgG aCL from 2 patients with APS… These patient-derived IgG monoclonal antibodies, and additional ones to be generated, may help define varying species of antibodies detected in aCL assays and identify the specific antibodies that may be pathogenic.
= = = = Extracted via Google:
“From patient 1, two monoclonals were obtained, designated IS3 and IS4. Combined with the two previously reported ones from this patient (i.e. IS1 and IS2)...”
http://www.ncbi.nlm.nih.gov/pubmed/10233371
http://pt.wkhealth.com/pt/re/bjha/abstract.00002328-199904000-00016.htm
B. Molecular Immunology, Oct.2002, Pgs.299-311
“Molecular and Genetic Characterizations of Five Pathogenic and Two Non-Pathogenic Monoclonal Antiphospholipid Antibodies”
Chukwuocha, Zhu, Cho, Visvanathan, Hwang, Rahman, Pojen P. Chen a
a Division of Rheumatology, Univ. of California, Los Angeles [UCLA]
ABSTRACT: We describe here the variable region genes of 7 IgG antiphospholipid antibodies derived from 2 APS patients. Of these, 5 are pathogenic as defined in a mouse model of thrombosis and 2 are not...
ARTICLE OUTLINE
… 3.1. Characterization of genes encoding mAb IS1 and IS2
3.2. Characterization of genes encoding mAb IS3
3.3. Characterization of genes encoding mAb IS4
3.4. Characterization of genes encoding mAb CL1
3.5. Characterization of genes encoding mAb CL15
3.6. Characterization of genes encoding mAb CL24 V genes …
Link via sciencedirect.com => http://tinyurl.com/5lhrcw

IV. P.Chen's IS1 & IS4 Mabs Neutralizes 7 Of 7 HIV Strains…
Pojen Chen's IS1 mab has shown some very interesting results. Here is an abstract from the ‘AIDS Vaccine 2007’ conf., Seattle, Aug20-23, 2007. The work was done by Haynes Duke/CHAVI/Gates team, along with, Pojen Chen.
Note: ‘AIDS Vaccine 2007’ was the 1st Conference to be organized under the auspices of the Global HIV Vaccine Enterprise (CHAVI/NIH & CAVD/Gates) - an alliance designed to promote innovation and collaboration to speed the search for an HIV vaccine.
P10-22 (pg. 27)
”Neutralization of HIV-1 Primary Isolates in PBMC Assays By Monoclonal Anti-Lipid Antibodies Derived from a Patient with Anti-Phospholipid Syndrome”
MA Moody [Tony Moody, Duke, Collab’ing w/PPHM as well – see http://tinyurl.com/657bqr ] 1, D Montefiori 1, MK Plonk 1, H Liao 1, S Xia 1, TC Gurley 1, SM Alam 1, P Chen 2 and BF Haynes 1
1=Duke Univ. Medical Center, Durham, NC
2=UCLA School of Medicine, Los Angeles, CA
BACKGROUND:
Rare human anti-envelope monoclonal antibodies (Mabs) that broadly neutralize HIV-1 have been made, but HIV-1+ or vaccinated subjects rarely make broadly reactive neutralizing antibodies. The observations that 2F5, 4E10 and 1b12 are polyspecific antibodies and that AIDS may be rare in patients with primary autoimmune diseases have prompted the hypothesis that patients with autoimmune diseases who have defects in tolerance mechanisms may be able to make antibodies that have anti-HIV-1 activity. Thus, we have assayed Mabs derived from anti-phospholipid syndrome patients for their ability to neutralize HIV-1.
METHODS:
IS1 & IS4 are human Mabs derived from a patient with antiphospholipid syndrome. Both are autoantibodies that react with cardiolipin & phosphatidylserine…
RESULTS:
IS1 & IS4 Mabs had no neutralizing activity against HIV-1 primary isolate pseudoviruses in the TZM/bl assay. In the PBMC assay, however, both IS1 & IS4 neutralized 7/7 primary isolates tested… By flow cytometry, neither Mab labeled viable uninfected T cell lines or PBMC; however, both IS1 & IS4 Mabs reacted strongly with the surface of virus infected T cells.
CONCLUSION:
Select anti-membrane polyspecific antibodies bind to HIV-1 infected but not uninfected cells, are non-pathogenic, and have anti-HIV-1 neutralizing activity in vitro in PBMC but not pseudovirus assays. It will be of interest to determine if such non-pathogenic antibodies are protective in passive therapy trials in vivo in non-human primates. Study of the mechanism of neutralization of these antibodies and their B cells of origin may provide clues to novel ways to safely induce protective antibodies to HIV-1.
Supported by the Center for HIV/AIDS Vaccine Immunology AI067854, CHAVI 005 protocol.
http://www.hivvaccineenterprise.org/_dwn/Late_Breaker_Abstracts.pdf

V. UCLA's Pojen Chen Mabs Appear In CHAVI Work
Pojen Chen and his anti-phospholipid mabs were first mentioned here in CHAVI-related work in this Sept 2007 CHAVI update:
CHAVI Y03 First Quarter Progress Report-Executive Summary
September 14, 2007
Barton Haynes, MD - CHAVI Director
10. ”Obtain human monoclonal antibodies from acutely infected HIV-1 patients and from autoimmune disease patients and determine their ability to neutralize HIV-1”.
Report: “James Robinson, David Montefiori, George Shaw and Lynn Morris comprise our team that is evaluating the specificities of the first neutralizing antibodies produced in acute HIV-1 infection, and have raised monoclonal antibodies that represent these antibodies. Tony Moody and Bart Haynes lead the studies in autoimmune disease patients, and with Pojen Chen at UCLA, have found human mabs from SLE and primary antiphospholipid syndrome patients that broadly neutralize HIV-1 primary isolates.”
http://www.chavi.org/modules/chavi_reports/index.php?id=17

VI. CHEN’s IS1 mab in BART HAYNES US PATENT APPLICATION…
An exciting patent application from Bart Haynes has recently hit the govt database (app #20080057075, filed 6-22-07, pub. 3-6-08):
“Method of Inducing Neutralizing Antibodies to HIV”
Inventor: Barton F. Haynes
Link to USPTO.gov => http://tinyurl.com/6oevsb
A few snips…
CLAIMS:
1. A method of treating HIV comprising administering to a patient in need thereof an antibody derivable from a normal subject or from an autoimmune disease subject that binds to a lipid on the surface of HIV or on the surface of HIV-infected cells and thereby neutralizes HIV-1, wherein said antibody is administered in an amount sufficient to effect said treatment.
2. The method according to claim 1 wherein said antibody is derivable from an anti-phospholipid syndrome subject.
3. The method according to claim 1 wherein said antibody is non-pathogenic.
4. The method according to claim 1 wherein said antibody is IS1, IS4 or IS6, or binding fragment thereof.
5. The method according to claim 1 wherein said antibody is IS1, or binding fragment thereof.
= = = =
[0108] Alving and colleagues have made a mouse mab against phosphatidyl inositol phosphate and have shown that it neutralizes HIV in a PBMC assay. What the present studies show is that humans can spontaneously make anti-lipid antibodies and that these antibodies can broadly neutralize HIV in an unprecedented manner.
[0109] Summarizing, autoimmune disease patients can make antibodies that bind to virus-infected cells and, presumably, to budding HIV virions by virtue of their reactivity to HIV membranes and host membranes. Certain anti-lipid antibodies from autoimmune disease patients can also react with the Envelope trimer (such as IS6) but not all of the antibodies react also with the trimer (i.e., IS1 and IS4 do not react). Therefore, reactivity with the HIV envelope is not a prerequisite for neutralization in these antibodies.
[0051] It will be appreciated from a reading of the foregoing that if HIV has evolved to escape the host immune response by making the immune system blind to it, other infectious agents may have evolved similarly. That is, this may represent a general mechanism of escape. That being the case, approaches comparable to those described herein can be expected to be useful in the treatment of such other agents well.