Filed on behalf of Patent Owner Genentech, Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Owen K. Allen (Reg. No. 71,118)
`Robert J. Gunther, Jr. (Pro Hac Vice to be filed)
`Lisa J. Pirozzolo (Pro Hac Vice to be filed)
`Kevin S. Prussia (Pro Hac Vice to be filed)
`Andrew J. Danford (Pro Hac Vice to be filed)
`WILMER CUTLER PICKERING
` HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`Adam R. Brausa (Reg. No.
`60,287)
`Daralyn J. Durie (Pro Hac Vice
`to be filed)
`Durie Tangri LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2017-01488
`Patent 6,407,213
`____________________________________________
`
`DECLARATION OF DR. LEONARD G. PRESTA
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`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2016
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`

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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`I, Dr. Leonard G. Presta, declare as follows:
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`I.
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`Background
`1.
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`I have over thirty years of experience in the biotechnology industry,
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`focusing on antibody and protein engineering.
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`2.
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`In 1976, I obtained my Bachelors of Science degrees in chemistry and
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`biology from the University of Arizona. In 1985, I obtained my Ph.D. in
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`biochemistry from Texas A&M University where the emphasis of my research was
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`on x-ray crystallography and molecular modeling. My thesis was titled, “Studies
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`of the interaction of peptide and non-peptide substrates and inhibitors with serine
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`proteases by computer modeling, molecular mechanics calculations and X-ray
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`crystallography.”
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`3.
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`After obtaining my Ph.D., I took a post-doctoral position in the group
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`of Dr. George Rose at Hershey Medical Center, Penn State University. In that
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`role, I continued to work on molecular modeling and focused specifically on
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`modeling of alpha-helix start/stop signals in protein sequences.
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`4.
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`In 1988, I joined Genentech as a molecular modeler in the Protein
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`Engineering Department. My initial role was to create computer models
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`representing proteins (whether actual or hypothetical) by using known information
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`about the proteins’ amino acid sequences and the crystal structures of related
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`proteins.
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`5.
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`, I began to apply my modeling skills and knowledge to
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`create a human consensus sequence for an antibody, with the idea that such a
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`consensus sequence could be used as a broadly-applicable framework to create
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`humanized antibodies. My efforts were successful, and I, along with my co-
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`inventor, Dr. Paul J. Carter, were awarded U.S. Patent No. 6,407,213 (“the ’213
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`patent) in connection with that work. As described in the ’213 patent, I created a
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`human consensus sequence, and in turn used it to “humanize” the murine 4D5
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`antibody, which inhibits proliferation of human tumor cells overexpressing
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`p185HER2 found in breast cancer. Our work led to Herceptin®, as well as other
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`therapeutics that use the humanization techniques of the ’213 patent, including
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`Perjeta®, Xolair®, Avastin®, and Lucentis®. The work is also documented in the
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`research paper, “Humanization of the anti-p185 antibody for human cancer
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`therapy,” published in Proc. Natl. Acad. Sci., Vol. 89, pp. 4285-4289, May 1992,
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`that I co-authored. (Ex. 2020.)
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`6.
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`I continued to work at Genentech as the Director of the Antibody
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`Technology Group until 2001. I have since held a number of positions including
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`Distinguished Fellow at Merck/Schering-Plough Biopharma, Executive Director of
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`Protein Engineering at Zymeworks, Inc., and consultancy positions with several
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`biotechnology companies.
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`7.
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`I am a named inventor on more than 150 U.S. patents, have published
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`extensively, and have served on the editorial boards of scientific journals,
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`including the Journal of Biological Chemistry, PROTEINS, and MABS.
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`8. My curriculum vitae, which has a list of my publications and
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`presentations, is attached as Appendix A.
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`II. Overview of Invention and Documentation
`9.
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`Below, I describe my contribution to the invention of the ’213 patent.
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`In connection with that work, I (1) created and proposed a human consensus
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`sequence for humanized antibodies; (2) determined rules for identifying framework
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`positions in the human consensus sequence that contribute to antibody binding
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`affinity and conformation; and (3) applied these concepts to propose amino acid
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`sequences for humanized 4D5 antibodies. By
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`, I had completed
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`each of these steps and provided to Dr. Carter proposed sequences for the heavy
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`and light chains of humanized 4D5 antibodies.
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`10. My work is documented in my laboratory notebooks and records,
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`which I kept in the ordinary course of my work at Genentech. Through my
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`employment with Genentech, I am familiar with Genentech’s practices regarding
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`the creation and maintenance of laboratory notebooks. Genentech’s library
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`provides researchers with laboratory notebooks, each of which has a unique
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`number and is filmed when completed. As was the general practice with
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`researchers at Genentech, I maintained laboratory notebooks to record progress on
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`my projects,
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` when I worked on
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`developing the human consensus sequence and proposing the humanized 4D5
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`sequences. Although much of my work involved computer modeling, it was my
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`general practice to record in my notebooks significant steps I took on any project.
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`I recorded those steps in my notebook on or around the time I took those steps—
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`whether by printing out a page from the computer or writing my analyses—and
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`signed and dated each page with that date. As a result, the dates recorded on my
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`laboratory notebook entries were made at or near the time they occurred.
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`11. Exhibit 2001 is a true and correct copy of my laboratory Notebook
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`10098,
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`. Exhibit 2002 is a true and
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`correct copy of my laboratory Notebook 10823,
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`. Other than when these notebooks were filmed by the
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`Genentech library
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`, they remained in my possession during
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`my employment with Genentech. When I left Genentech, I provided Genentech’s
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`records department with the original notebooks. As I describe below, the steps I
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`took to develop a human consensus sequence and proposed humanized 4D5
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`sequences are documented in my notebooks.
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`12.
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` In addition to these notebooks, I also kept three-ring binders with
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`materials relating to my projects. It was my general practice to print out emails
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`and memos I received that discuss the status or milestones of my projects and
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`include them in a binder. I printed out and/or included emails and/or memos as
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`received; I did not change or alter their content in any manner. My emails and
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`other computer files discussed below include correspondence from Dr. Carter
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`dated
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` informing me that he had expressed the humanized 4D5 Fab
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`of one of my proposed sequences (Ex. 2011).
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`III. Background on Antibodies
`13. An antibody is a protein produced by the immune system. An
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`antibody binds to foreign substances that enter the body, known as “antigens,”
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`which helps the immune system to respond to the foreign substance including
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`removing it from the body.
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`14. An antibody consists of four polypeptide chains: two identical heavy
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`chains and two identical light chains. The two heavy chains and two light chains
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`bind together to form an antibody’s characteristic “Y” shape, which is held
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`together and formed by interactions between certain amino acids on each chain.
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`15. The immune system is capable of generating at least millions of
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`antibodies with differing specificity, each recognizing and binding to different
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`antigens. This variability is due to the specific amino acid sequence making up
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`each antibody. In particular, the heavy chains and light chains of an antibody
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`contain both a “variable” domain and a “constant” domain. The constant domain
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`is generally conserved across all antibodies within a particular IgG sub-class (i.e.,
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`IgG1, IgG2, IgG3, IgG4), meaning that it has few, if any, amino acid differences
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`across different antibodies in the same sub-class. The variable domain is
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`responsible for binding to the antigen, and consists of three “complementarity
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`determining regions,” or CDRs, interspersed between four “framework regions,” or
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`FRs. The CDRs are highly variable and form the antigen binding site when the
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`antibody is properly folded. In comparison, the FRs are largely conserved among
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`each subgroup within an IgG sub-class (but not as conserved as the constant
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`domain).
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`16. Prior to the invention of the ’213 patent, antibodies that target a
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`particular antigen could be obtained by exposing an animal—such as a mouse—to
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`an antigen. However, when repeatedly administered to a human, these murine
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`antibodies are attacked by the human immune system through an immunogenic
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`response known as a “human anti-mouse antibody,” or HAMA, response.
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`17. The first efforts to address the HAMA response involved making
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`chimeric antibodies—antibodies with human constant regions, and rodent variable
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`regions (or a portion of the variable region). However, those chimeric antibodies
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`often still resulted in an immunogenic response.
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`18. To address that immunogenic response, scientists developed
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`techniques to “humanize” antibodies obtained from non-human sources. Those
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`techniques involved incorporating the CDRs from a non-human antibody into a
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`human antibody sequence that was chosen to be similar to the non-human
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`antibody.
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`19. The following is a diagram of a generic humanized antibody. This
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`diagram was part of a poster for the Proteins Gordon Conference in 1991, on which
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`I am an author.
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`20. As shown in the diagram above, the CDRs are colored in black, and
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`the FRs are the white areas before and after each CDR. A mouse antibody is
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`“humanized” by inserting mouse CDRs in place of the human CDRs in a human
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`antibody sequence.
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`21.
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`In general, it was difficult to simply replace the human CDRs with
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`mouse CDRs and obtain a resulting humanized antibody that both did not cause an
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`immunogenic response and that also retained high affinity for the desired antigen.
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`This problem was caused by the fact that scientists were learning that certain FR
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`residues, while not within the CDRs, nonetheless contributed to antibody structure
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`and specificity. Scientists therefore proposed substitution of certain FR residues in
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`addition to the CDRs to obtain an antibody with the desired specificity. This
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`history of humanized antibodies is described in the ’213 patent at column 2, line 21
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`to column 3, line 8.
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`IV. The Invention of the ’213 Patent
`22.
`, I was working at Genentech as a molecular modeler in
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`Genentech’s Protein Engineering Department. By that time, I had already worked
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`on several projects at Genentech to create computer three-dimensional models of
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`proteins such as CD4 and tissue plasminogen activator, using known information
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`of the protein’s amino acid sequence and the crystal structures of related proteins.
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`23. Dr. Paul Carter approached me about using modeling to humanize a
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`murine antibody. Dr. Carter had previously worked in Dr. Gregory Winter’s
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`laboratory. Dr. Winter had published some of the early research describing
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`grafting murine CDRs into human variable domains. Dr. Carter and I were also
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`aware of work by scientists at the Protein Design Labs, which described a
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`humanized antibody prepared starting from the human variable domain sequence
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`that was the most homologous, or “best fit,” to the original murine antibody. Dr.
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`Carter and I made a conscious choice to avoid following the humanization
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`techniques developed by others at the time. I instead decided to develop a new
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`way of humanizing a murine antibody by creating a human “consensus” variable
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`domain sequence, which relies upon a human sequence as the starting point for
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`humanizing an antibody.
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`24.
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`I believed that this “consensus” sequence approach would have
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`several advantages over the prior approaches. For example, the concept of a
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`consensus sequence could be used when humanizing almost any antibody. That
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`would greatly improve the speed of humanizing antibodies; by contrast, the prior
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`art “best fit” approach required identifying a unique human sequence that was
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`similar to the murine antibody as a starting point. I also believed that starting from
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`a broadly-applicable consensus sequence might improve the stability and
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`manufacturability of the resulting humanized antibodies. In addition, I believed
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`that using a consensus sequence approach would result in a lower risk of
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`immunogenicity as compared to other humanization techniques, especially given
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`that a humanized antibody therapeutic had yet to be approved by the FDA.
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`Published antibody sequences are based upon antibodies obtained from a single
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`individual and thus may contain unique variations specific to that individual, which
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`may result in immunogenicity when used in other people. By starting with a
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`broadly-applicable “consensus” sequence consisting of the most common amino
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`acid residues at each position based on numerous published antibody sequences, I
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`reduced the possibility of starting from a human sequence containing unusual
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`residues that may induce an immunogenic response.
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`25.
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`Declaration of Dr. Leonard G. Presta
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`26.
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`Declaration of Dr. Leonard G. Presta
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`29.
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`31.
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`33.
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`36.
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`37.
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`Declaration of Dr. Leonard G. Presta
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`Declaration of Dr. Leonard G. Presta
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`IPR2017-01488
`Declaration of Dr. Leonard G. Presta
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`51. HuMAb4D5-8 is the humanized 4D5 antibody that became the drug
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`Herceptin®, and includes the murine CDRs with substitutions at 55L, 66L, 71H,
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`73H, 78H, 93H, 102H.
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`52. Dr. Carter’s and my invention was also used in several other human
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`therapeutics. For example, it was used in creating Avastin®, which includes
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`substitutions at 49H, 69H, 71H, 73H, 76H, 78H, 94H, and 46L. (See Ex. 2021.)
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`53.
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`I have reviewed the claims of the ’213 patent. In view of the
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`information described above and the exhibits submitted herewith, I possessed the
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`invention recited in claims 1-2, 4, 12, 25, 29-31, 33, 42, 60, 62-67, 69, and 71-81
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`before July 26, 1990 as confirmed by my development before that date of several
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`humanized antibodies applying our invention, including HuMAb4D5-5 and
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`HuMAb4D5-8.
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`Declaration of Dr. Leonard G. Presta
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`IPR2017-01488
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`I declare under penalty ofperjury of the laws of the United States of
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`America that the foregoing is true and correct.
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`Date: August Q? 2017
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`Dr. Leonard G. gresta
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`431—
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`(cid:36)(cid:51)(cid:51)(cid:40)(cid:49)(cid:39)(cid:44)(cid:59)(cid:3)(cid:36)
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`APPENDIX A
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`32
`32
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`

`

`LEONARD GEORGE PRESTA
`
`1900 Gough St., Apt. 206
`San Francisco, CA 94109
` (415) 922-2637
`e-mail:
`leonard.presta@gmail.com
`
`Synopsis of Experience
`
`
` •
`
` More than 30 years of experience in the biotechnology industry, primarily in
` protein/antibody engineering.
`• At Genentech, I was responsible for the protein engineering that led to a series of
` marketed therapeutic monoclonal antibodies - Herceptin, Raptiva, Xolair, Avastin,
` Lucentis, Perjeta and therapeutic protein Tenecteplase.
`• At Merck (formerly Schering-Plough), I was responsible for protein and antibody
` engineering of all internal therapeutic antibodies in the pipeline.
`• Published extensively in peer-reviewed journals, an inventor on 150 U.S.
` patents, and an editorial board member (past or present) for Journal of Biological
` Chemistry, PROTEINS, and MABS
`
`Education:
`Ph.D.
`Biochemistry and Biophysics, Texas A&M University, 1985
`B.S.
`Chemistry, cum laude, University of Arizona, 1976
`B.S.
`Biology, cum laude, University of Arizona, 1976
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`Research and Professional Experience:
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`2015-present
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`2013-present
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`Zymeworks, Inc
`Executive Director of Protein Engineering
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`Consultant:
`IGM Biosciences, Inc.
`BioMarin, Inc.
`GenScript, Inc.
`Igenica, Inc.
`Compugen, Inc.
`Alector, Inc.
`Calibr
`Cellerant, Inc.
`CytomX, Inc.
`Iconic Therapeutics, Inc.
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`33
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`2007-2012
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`2005-2010
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`2001-2007
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`2000-2001
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`1999-2001
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`1996-1999
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`1993-1995
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`Distinguished Fellow
`Merck/Schering-Plough Biopharma
`Responsible for design and protein engineering of therapeutic antibodies and
`auxiliary antibodies used for animals models (e.g., murinized, cynoized
`antibodies) and bispecific antibodies and other new antibody formats. Total of
`4 Ph.D. and 10 B.S./M.S. direct/indirect reports.
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`Editorial Board, Journal of Biological Chemistry
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`Senior Director, Protein Engineering
`Schering-Plough Biopharma (formerly DNAX Research Institute)
`Department responsible for generation and production of research and
`therapeutics proteins, primarily antibodies; includes six groups
`specializing in antibody generation (hybridoma/phage library),
`molecular biology (plasmid and vector generation), protein expression and
`purification, assay development, proteomics and protein engineering. Total of
`8 Ph.D. and 21 B.S./M.S. direct/indirect reports.
`
`Director, Antibody Technology Group
`Genentech, Inc.
`Generation of antibodies for use as reagents and
`therapeutics for Genentech Research and Development
`Direct reports: one Senior Scientist, one Scientist;
`total of 20 direct/indirect reports in group
`
`Staff Scientist, Dept. of Immunology
`Genentech, Inc.
`Molecular modeling, engineering and structure-function
`studies on proteins, with emphasis on immunoglobulins,
`Fc receptors, neurotrophins and neurotrophin
`receptors, intercellular adhesion molecules
`Direct reports: two postdoctoral positions; two Senior
`Research Assistants; five Research Assistants; one
`Scientist.
`
`Senior Scientist, Dept. of Immunology
`Genentech, Inc.
`Molecular modeling, engineering and structure-function
`studies on proteins, with emphasis on immunoglobulins,
`Fc receptors, neurotrophins and neurotrophin
`receptors, intercellular adhesion molecules; two postdoctoral positions;
`six Research Assistants.
`
`Senior Scientist, Dept. of Protein Engineering,
`Genentech, Inc.
`Molecular modeling, engineering and structure-function
`studies on proteins, with emphasis on immunoglobulins,
`neurotrophins and neurotrophin receptors; two
`postdoctoral positions; three Research Assistants.
`
`34
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`1991-2007
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`1988-1992
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`
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`1986-1988
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`1982-1984
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`1980-1982
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`1977-1980
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`
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`Editorial Board, PROTEINS: Structure, Function, and
`Genetics
`
`Scientist, Dept. of Protein Engineering,
`Genentech, Inc.
`Molecular modeling, engineering and structure-function
`studies on proteins, with emphasis on immunoglobulins
`and serine proteases; two Research Assistants.
`
`Postdoctoral Fellow with Dr. George Rose, Dept. of
`Biological Chemistry, Pennsylvania State
`University Medical Center
`Theoretical studies on protein folding; helix signals in
`proteins.
`
`Lecturer, Dept. of Biochemistry and Biophysics,
`Texas A&M University
`Teaching and coordinating undergraduate senior-
`level biochemistry laboratory courses with four
`teaching assistants and 200 students.
`
`Teaching Assistant, Dept. of Biochemistry and
`Biophysics, Texas A&M University
`Assisted faculty in biochemistry laboratory course.
`
`Technical Assistant, Analytical-Organic Section,
`Illinois Institute of Technology Research Institute
`Development of computer programs for processing
`gas chromatography-mass spectrometer data;
`studies on vapor phase hydrolysis of chloroacetyl
`chlorides (air pollution).
`
`Doctoral Dissertation:
`Interactive Computer Graphics Modeling and Molecular Mechanics Calculations of
`Protein-Ligand Interactions. Studies of the interaction of peptide and non-peptide substrates and
`inhibitors with serine proteases by computer modeling, molecular mechanics calculations and X-ray
`crystallography.
`
`Publications:
`
`Murphy, J.T., Burey, A.P., Beebe, A.M., Gu, D., Presta, L.G., Merghoub, T., Wolchok,
`J.D. Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in
`mice. Blood 123:2172-2180 (2014)
`
`Lu, Y, Vernes, J.M., Chiang, N., Ou, Q., Ding, J., Adams, C., Hong, K., Truong, B.T., Ng,
`D., Shen, A., Nakamura, G., Gong, Q., Presta, L.G., Beresini, M., Kelley, B., Lowman,
`
`35
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`

`H., Wong, W.L., Meng, Y.G. Identification of IgG(1) variants with increased affinity to
`FcgRIIIA and unaltered affinity to FcgRI and FcRn: comparison of soluble receptor-
`based and cell-based binding assays. J. Immunol. Methods 365:132-141 (2011)
`
`Presta, L.G. Molecular engineering and design of therapeutic antibodies. Curr. Opin.
`Immunol. 20:460-470 (2008)
`
`Presta, L. Evolving an anti-toxin antibody. Nat. Biotchnol. 25:63-65 (2007)
`
`Chen, Y., Langrish, C.L., McKenzie, B., Joyce-Shaikh, B., Stumhofer, J.S., McClanahan,
`T., Blumenschein, W., Churakova, T., Low, J., Presta, L., Hunter, C.A., Kastelein, R.A.,
`Cua, D.J. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates
`autoimmune encephalomyelitis. J. Clin. Invest. 116:1317-1326 (2006)
`
`Petkova, S.B., Akilesh S., Sproule T.J., Christianson, G.J., Al Khabbaz, H., Brown, A.C.,
`Presta, L.G., Meng, Y.G., Roopenian D.C. Enhanced half-life of genetically engineered
`human IgG1 antibodies in a humanized FcRn mouse model: potential application in
`humorally mediated autoimmune disease. Intl. Immunol. 18:1759-1769 (2006)
`
`Presta, L.G. Engineering of therapeutic antibodies to minimize immunogenicity and
`optimize function. Adv. Drug Delivery Rev. 58:640-656 (2006)
`
`Adams, C.W., Allison, D.E., Flagella, K., Presta, L., Clarke, J., Dybdal, N., McKeever,
`K., Sliwkowski, M.X. Humanization of a recombinant monoclonal antibody to produce a
`therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol. Immunother.
`55:717-727 (2006)
`
`Presta, L.G. Selection, design, and engineering of therapeutic antibodies. J. Allergy
`Clin. Immunol. 116:731-736 (2005)
`
`Wang, Y., Hailey, J., Williams, D., Wang, Y., Lipari, P., Malkowski, M., Wang, X., Xie,
`L., Li, G., Saha, D., Ling, W.L., Cannon-Carlson, S., Greenberg, R., Ramos, R.A.,
`Shields, R., Presta, L., Brams, P., Bishop, W.R., Pachter, J.A. Inhibition of insulin-like
`gorwth factor-I receptor (IGF-IR) signaling and tunor cell growth by a fully human
`neutralizing anti-IGF-IR antibody. Mol. Cancer Ther. 4:1214-1221 (2005)
`
`Hong, K., Presta, L.G., Lu, Y., Penn, A., Adams, C., Chuntharapai, A., Yang, J., Wong,
`W.L., Meng, Y.G. Simple quantitative live cell and anti-idiotypic antibody based ELISA
`for humanized antibody directed to cell surface protein CD20. J. Immunol. Meth.
`294:189-197 (2004)
`
`Presta, L. Antibody engineering for therapeutics. Curr. Opin. Struct. Biol. 13:519-525
`(2003)
`
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`

`Eigenbrot, C., Meng, Y.G., Krishnamurthy, R., Lipari M.T., Presta, L., Devaux, B., Wong,
`T., Moran, P., Bullens, S., Kirchhofer, D. Structural insight into how an anti-idiotypic
`antibody against D3H44 (anti-tissue factor antibody) restores normal coagulation. J.
`Mol. Biol. 331:433-446 (2003)
`
`Miller, K., Meng, G., Liu, J., Hurst, A., Hsei, V., Wong, W-L., Ekert, R., Lawrence, D.,
`Sherwood, S., DeForge, L., Gaudreault, J., Keller, G., Sliwkowski, M., Ashkenazi, A.,
`Presta, L. Design, construction, and in vitro analyses of multivalent antibodies.
`J. Immunol. 170:4854-4861 (2003)
`
`Presta, L.G. Celebrating diversity and mimicking maturation. Nat. Biotechnol.
`20:1096-1097 (2002)
`
`Presta, L.G., Shields R.L. Understanding the binding of IgE to its high-affinity receptor
`and to an anti-IgE antibody. In: IgE and Anti-IgE Therapy in Asthma and Allergic
`Disease, Fick, R.B.Jr. & Jardieu, P.M. (eds.), Dekker, New York, 2002, pp.23-38
`
`Presta, L.G., Shields, R.L., Namenuk, A.K., Hong, K., Meng, Y.G.
`Engineering therapeutic antibodies for improved function. Biochem. Soc. Trans.
`30:487-490 (2002)
`
`Presta, L.G. Engineering antibodies for therapy. Curr. Pharm. Biotechnol. 3:237-256
`(2002)
`
`Vajdos, F.F., Adams, C.W., Breece, T.N., Presta, L.G., de Vos, A.M., Sidhu, S.S.
`Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody
`obtained with shotgun scanning mutagenesis. J. Mol. Biol. 320:415-428 (2002)
`
`Shields, R.L., Lai, J., Keck, R., O'Connell, L.Y., Hong, K., Meng, Y.G., Weikert, S.H.A.,
`Presta, L.G. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to
`human FcγRIII and antibody-dependent cellular toxicity. J. Biol. Chem.
`277:26733-26740 (2002)
`
`Gadek, T.R., Burdick, D.J., McDowell, R.S., Stanley, M.S., Marsters J.C. Jr., Paris, K.J.,
`Oare, D.A., Reynolds, M.E., Ladner, C., Zioncheck, K.A., Lee, W.P., Gribling, P., Dennis,
`M.S., Skelton, N.J., Tumas, D.B., Clark, K.R., Keating, S.M., Beresini, M.H., Tilley,
`J.W., Presta, L.G., Bodary, S.C. Generation of an LFA-1 antagonist by the transfer of the
`ICAM-1 immunomodulatory epitope to a small molecule. Science 295:1086-1089 (2002)
`
`Faelber, K., Kirchhofer, D., Presta, L., Kelley, R.F., Muller, Y.A.
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`The 1.85 Å resolution crystal structures of tissue factor in complex with humanized Fab
`D3H44 and of free humanized Fab D3H44: revisiting the solvation of antigen combining
`sites. J. Mol. Biol. 313:83-97 (2001)
`
`Leong, S.R., DeForge, L., Presta, L., Gonzalez, T., Fan, A., Reichert, M., Chuntharapai,
`A., Kim, J.K., Tumas, D.B., Lee, W.P., Gribling, P., Snedecor, B., Chen, H., Hsei, V.,
`Schoenhoff, M., Hale, V., Deveney, J., Koumenis, I., Shahrokh, Z., McKay, P., Galan, W.,
`Wagner, B., Narindray, D., Hebert, C., Zapata, G. Adapting pharmacokinetic properties of
`a humanized anti-interleukin-8 antibody for therapeutic applications using site-directed
`pegylation. Cytokine 16:106-119 (2001)
`
`Chuntharapai, A., Lai, J., Huang, X., Gibbs, V., Kim, K.J., Presta, L.G., Stewart, T.A.
`Characterization and humanization of a monoclonal antibody that neutralizes human
`leukocyte interferon: a candidate therapeutic for IDDM and SLE. Cytokine 15:250-260
`(2001)
`
`Shields, R.L., Namenuk, A.K., Hong, K., Meng, Y.G., Rae, J., Briggs, J., Xie, D., Lai, J.,
`Stadlen, A., Li, B., Fox, J.A., Presta, L.G. High resolution mapping of the binding site on
`human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn and design of IgG1 variants with
`improved binding to the FcγR. J. Biol. Chem. 276:6591-6604 (2001)
`
`Presta, L., Sims, P., Meng, Y.G., Moran, P., Bullens, S., Bunting, S., Schoenfeld, J.,
`Lowe, D., Lai, J., Rancatore, P., Iverson, M., Lim, A., Chisholm, V., Kelley, R.F.,
`Riederer, M., Kirchhofer, D. Generation of a humanized, high affinity anti-tissue factor
`antibody for use as a novel antithrombotic therapeutic. Thrombosis & Haemostasis
`85:379-389 (2001)
`
`Idusogie, E.E., Wong, P.Y., Presta, L.G., Gazzano-Santoro, H., Totpal, K., Ultsch, M.,
`Mulkerrin, M.G. Engineered antibodies with increased activity to recruit complement. J.
`Immunol. 166:2571-2575 (2001)
`
`Poston, R.S., Robbins, R.C., Chan, B., Simms, P., Presta, L., Jardieu, P., Morris, R.E.
`Effects of humanized monoclonal antibody to rhesus CD11a in rhesus monkey cardiac
`allograft recipients. Transplantation 69:2005-2013 (2000)
`
`Idusogie, E.E., Presta, L.G., Gazzano-Santoro, H., Totpal, K., Wong, P.Y., Ultsch, M.,
`Meng, Y.G., Mulkerrin, M.G. Mapping of the C1q binding site on rituxan, a chimeric
`antibody with a human IgG1 Fc. J. Immunol. 164:4178-4184 (2000)
`
`Clynes, R.A., Towers, T.L., Presta, L.G., Ravetch, J.V. Inhibitory Fc receptors modulate
`in vivo cytotoxicity against tumor targets. Nature Medicine 6:443-446 (2000)
`
`38
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`O’Connell, L.; Hongo, J.-A.; Presta, L.G.; Tsoulfas, P. TrkA amino acids controlling
`specificity for nerve growth factor. J. Biol. Chem. 275:7870-7877 (2000)
`
`Edwards, C.P.; Fisher, K.L.; Presta, L.G.; Bodary, S.C. Mapping the intercellular
`adhesion molecule-1 and -2 binding site on the inserted domain of leukocyte function-
`associated antigen-1. J. Biol. Chem. 273:28937-28944 (1998)
`
`Merchant, A.M.; Zhu, Z.; Yuan, J.Q.; Goddard, A.; Adams, C.W.; Presta, L.G.; Carter, P.
`An efficient route to human bispecific IgG. Nature Biotechnology 16:677-681 (1998)
`
`O'Connor, S.J.; Meng, Y.G.; Presta, L.G. Humanization of an antibody against human
`protein C and calcium-dependence involving framework residues. Protein Engineering
`11:321-328 (1998)
`
`Urfer, R.; Tsoulfas, P.; O’Connell, L.; Hongo, J.-A.; Zhao, W.; Presta, L.G. High
`resolution mapping of the binding site of trkA for nerve growth factor and trkC for
`neurotrophin-3 on the second immunoglobulin-like domain of the trk receptors. J. Biol.
`Chem. 273:5829-5840 (1998).
`
`Davis-Smyth, T., Presta, L.G., Ferrara, N. Mapping the charged residues in the second
`immunoglobulin-like domain of the vascular endothelial growth factor/placenta growth
`factor receptor Flt-1 required for binding and structural stability. J. Biol. Chem.
`273:3216-3222 (1998)
`
`Presta, L.G.; Chen, H.; O'Connor, S.J.; Chisolm, V.; Meng, G.Y.; Krummen, L.; Winkler,
`M.; Ferrara, N. Humanization of an anti-vascular endothelial growth factor monoclonal
`antibody for the therapy of solid tumors and other disorders. Cancer Research
`57:4593-4599 (1997).
`
`Fong, S.; Jones, S.; Renz, M.E.; Chiu, H.H.; Ryan, A.M.; Presta, L.G.; Jackson, D.
`Mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Its binding motif for α4β7
`and role in experimental colitis. Immunologic Res. 16:299-311 (1997).
`
`Pearce, K.H. Jr.; Potts, B.J.; Presta, L.G.; Bald, L.N.; Fendly, B.M.; Wells, J.A.
`Mutational analysis of thrombopoietin for identification of receptor and neutralizing
`antibody sites. J. Biol. Chem. 272:20595-20602 (1997).
`
`Urfer, R.; Tsoulfas, P.; O'Connell, L.; Presta, L.G. Specificity determinants in
`neurotrophin-3 and the design of nerve growth factor-based trkC agonists by changing
`central β-strand bundle residues to their neurotrophin-3 analogs. Biochemistry
`36:4775-4781 (1997).
`
`39
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`

`Zhu, Z.