04-5223. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by contacting Brenda Hefti, Ph.D., Technology Licensing Specialist, Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: [phone]; fax: [phone]; e-mail: [e-mail]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

LMB-2, An Immunotoxin That Shows Efficacy in Phase I Clinical Trials in Treating Patients With Chemotherapy-Resistant Hairy Cell Leukemia and Other Hematologic Malignancies

A number of patents and patent applications cover this technology, including but not limited to:

“Reduction of the nonspecific animal toxicity of immunotoxins by mutating the framework regions of the Fv to lower the isoelectric point,” PCT/US01/43602, by Pastan, Onda, Nagata, Tsutsumi, Vincent, Kreitman, Vasmatzis, and Lee. (DHHS Ref. E-146-1999/0); and

“Recombinant antibody-toxin fusion protein,” PCT/US90/02097, U.S. Patents 6,051,405, 5.863,745, and 5,696,237, by Fitzgerald, Chaudhary, Pastan, and Waldmann. (DHHS Ref. E-135-1989/0)

The invention provides a recombinant immunotoxin, LMB-2 [anti-Tac(Fv)-PE38], that has been used in Phase I trials to treat hematologic malignancies. The antibody portion of the immunotoxin is an Fv fragment (antigen-binding fragment) of the anti-Tac antibody, and it is fused to truncated Pseudomonas Exotoxin (PE38). This immunotoxin has been used in a Phase I clinical trial (Kreitman et al., 2000; J Clin Oncol 18:1622-1636). Thirty five (35) patients with CD25-expressing hematologic malignancies, for whom standard and salvage therapies failed, were treated with LMB-2. All four patients with hairy cell leukemia (HCL) responded to treatment, and one patient achieved a complete remission that lasted for more than 20 months. Seven partial responses were observed; including responses in patients with cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2- to 5-log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly.

Several improvements on the original immunotoxin have been made (and are also the subject of patents and patent applications). One is the replacement of the single chain Fv with a more stable disulfide stabilized Fv. Another is recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. Still another discloses a polyethylene glycol modified form that is less immunogenic and has a longer half life in animals.

BL22, An Immunotoxin That Shows Efficacy in Clinical Trials in Treating Patients With Chemotherapy-Resistant Hairy Cell Leukemia, and Ha22, a Newly Engineered Immunotoxin, Which Shows Improved Cytotoxic Activity Over BL22

A number of patents and patent applications cover this technology, including but not limited to:

“Reduction of the nonspecific animal toxicity of immunotoxins by mutating the framework regions of the Fv to lower the isoelectric point,” PCT/US01/43602, by Pastan, Onda, Nagata, Tsutsumi, Vincent, Kreitman, Vasmatzis, and Lee. (DHHS Ref. E-146-1999/0);

“Immunotoxin containing a disulfide-stabilized antibody fragment joined to a Pseudomonas Exotoxin that does not require proteolytic activation,” PCT/US94/06678, by Pastan and Kuan. (DHHS Ref. E-163-1993/0,1);

“Recombinant antibody-toxin fusion protein,” PCT/US90/02097, U.S. Patents 6,051,405, 5.863,745, and 5,696,237, by Fitzgerald, Foudhary, Pastan, and Waldmann. (DHHS Ref. E-135-1989/0); and

“PEGylation of linkers improves antitumor activity and decreases toxicity of immunoconjugates,” PCTUS01/18503, by Pastan, Tsutsumi, Onda, Nagata, Lee and Kreitman. (DHHS Ref. E-216-2000/2)

The invention provides recombinant immunotoxins one of which has been used in a clinical trial to treat hematologic malignancies. The antibody portion of the parental immunotoxin is an anti-CD22 RFB4(dsFv) antibody or antigen-binding fragment, and it is fused to truncated Pseudomonas Exotoxin (PE38), creating the BL22 immunotoxin.

BL22 has been used in a phase I clinical trial for CD22 expressing malignancies and a high complete response rate observed in refractory Hairy Cell Leukemia (HCL). Of 16 cladribine-resistant patients, 11 had a complete remission and 2 had a partial remission with BL22 (Kreitman et al., N Engl J Med. 2001 Jul 26;345(4):241-7). Further responses have been observed since this publication and a phase 2 trial in HCL has just opened. Phase 2 trials in CLL and pediatric ALL should open soon.

HA22 is an improved form of BL22 with mutations in the antibody portion that increase its binding affinity for CD22 and its ability to kill cells from patients with low CD22 expression as occurs in CLL.

Several improvements on the original immunotoxin are also disclosed in these patents and patent applications. One of these is an application disclosing recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. Another generally discloses several different immunotoxins that might prove useful in treating hematological malignancies. Still another discloses methods of increasing immunotoxin stability by connecting the antibody chains with a disulfide bond.

Dated: March 2, 2004.

Steven M. Ferguson,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.