(12) United States Patent
`Dedrick et al.
`
`(54) TREATMENT METHOD
`
`(75)
`
`Inventors: Russell L. Dedrick, Kensington, CA
`(US); Marvin R. Garovoy, San
`Anselmo, CA (US); Susan M. Kramer,
`San Francisco, CA (US); Karen M.
`Starko, Hillsborough, CA (US)
`
`(73) Assignees: Genentech, Inc., South San Francisco,
`CA (US); XOMA Technology, Ltd.,
`Berkeley, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/819,921
`
`(22) Filed:
`
`Mar. 28, 2001
`
`Related U.S. Application Data
`
`(62) Division of application No. 09/527,957, filed on Mar. 17,
`2000, now abandoned.
`(60) Provisional application No. 60/125,228, filed on Mar. 19,
`1999, and provisional application No. 60/125,351, filed on
`Mar. 19, 1999.
`
`Int. Cl.7 .............................................. A61K 39/395
`(51)
`(52) U.S. Cl. ................................ 424/133.1; 424/173.1;
`424/144.1; 424/154.1
`(58) Field of Search ........................... 424/144.1, 130.1,
`424/143.1, 152.1, 153.1, 154.1, 173.1, 133.1
`
`(56)
`
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`
`8815518
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`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`
`US006582698Bl
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`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,582,698 Bl
`Jun.24,2003
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`(List continued on next page.)
`
`Primary Examiner-Christina Chan
`Assistant Examiner-Maher Haddad
`(74) Attorney, Agent, or Firm-Lee Tan
`
`(57)
`
`ABSTRACT
`
`A method is provided for reducing the occurrence of fever,
`headache, nausea and/or vomiting associated with adminis(cid:173)
`tration of a therapeutic compound to a mammal in need
`thereof, comprising administering to the mammal a first
`conditioning dose of a non-target cell depleting compound
`which binds to a cell surface receptor on a target mammalian
`cell; and administering a second therapeutic dose of the
`compound, wherein the second dose is higher than the first
`dose.
`
`8 Claims, 10 Drawing Sheets
`
`1 of 27
`
`PENN EX. 2049
`CFAD V. UPENN
`IPR2015-01836
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`

`
`US 6,582,698 Bl
`Page 2
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`* cited by examiner
`
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`
`-28
`1--/\
`
`Other Rx
`Discontinued
`
`Group
`(n)
`
`A (4)
`
`B (6)
`
`c (17)
`
`D (6)
`
`E (6)
`
`Study Day
`
`0
`
`7
`
`14
`
`21
`
`28
`
`35
`
`42
`
`49
`
`Primary
`Endpoint
`56
`
`A
`
`A
`
`A
`
`A
`
`A
`
`A
`
`A
`
`A
`
`- Dose (mg/kg)
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.1
`
`0.3
`
`0.3
`
`0.3
`
`0.3
`
`0.3
`
`0.3
`
`0.3
`
`0.4
`
`0.6
`
`0.6
`
`0.6
`
`0.6
`
`0.1
`
`0.1
`
`0.3
`
`0.6
`
`0.3
`
`0.4
`
`0.6
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`Figure 1
`
`d •
`\JJ.
`•
`~
`~ ......
`~ = ......
`
`/
`
`90
`I
`
`...,
`
`Follow-up
`(A Monthly)
`
`~
`
`~
`
`N
`~,J;;..
`N c
`8
`
`'Jl =(cid:173)~
`~
`""" 0
`"""
`""" c
`
`e
`
`rJ'J.
`O'I
`11.
`~
`
`N °' \0
`
`~
`~
`lo-"
`
`4 of 27
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`

`
`Group
`
`A
`
`B
`c
`
`D
`
`E
`
`Dose
`(mg/kg)
`
`0.1/qow
`
`0.1
`
`0.3*
`
`0.3-0.6
`
`0.3-1.0
`
`n
`
`4
`
`6
`
`Day 0
`
`Day 28
`
`Day56
`
`23.6 ± 8.1
`
`-11.3 ± 15.1
`
`-4.6 ± 5.6
`
`21.2 ± 6.5
`
`-8.2 ± 15.1
`
`-14.1 ± 17.0
`
`17
`
`25.6 ± 7.4
`
`-24.5 ± 21.7
`
`-40.4 ± 28.1
`
`6
`
`6
`
`23.8 ± 4.5
`
`-30.1 ± 13.7
`
`-39.6 ± 28.9
`
`28.1 ± 6.1
`
`-38.6 ± 16.7
`
`-45.4 ± 31.2
`
`Total
`
`39
`
`24.8 ± 6.8
`
`-23.7 ± 20.0
`
`-33.2 ± 28.4
`
`d •
`\JJ.
`•
`~
`~ ......
`~ = ......
`
`~ = ?
`
`N
`~,J;;..
`
`N c c
`
`~
`
`'Jl =-~
`~ .....
`N
`0 .....,
`'"""' c
`
`Figure 2
`
`e
`
`rJ'J.
`O'I
`11.
`~
`
`N °' \0
`
`~
`~
`lo-"
`
`5 of 27
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`

`
`hu1124
`Dose Groups
`(combined)
`
`Dose
`(mg/kg)
`
`0/o Decrease in PASI Score
`Mean (±S.D)
`
`A+B
`
`0.1
`
`10.3 (± 13.9)
`
`C+D+E
`
`> 0.3
`
`41.3 (± 27.9)
`
`p value
`
`.0019
`
`Figure 3
`
`d •
`\JJ.
`•
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`~ ......
`~ = ......
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`~ = ?
`
`N
`.i;;..
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`'"""' c
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`e
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`lo-"
`
`6 of 27
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`
`U.S. Patent
`
`Jun.24,2003
`
`Sheet 4of10
`
`US 6,582,698 Bl
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`PENN EX. 2049
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`IPR2015-01836
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`

`
`U.S. Patent
`
`Jun.24,2003
`
`Sheet 5of10
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`Jun.24,2003
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`Jun.24,2003
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`U.S. Patent
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`Jun.24,2003
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`Jun.24,2003
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`Sheet 10 of 10
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`1
`TREATMENT METHOD
`
`REFERENCE TO RELATED APPLICATIONS
`
`This is a divisional application of application Ser. No.
`09/527,957 (now abandoned), filed on Mar. 17, 2000, which
`claims priority under U.S.C. §119(e) to provisional patent
`applications Serial No. 60/125,228 and Serial No. 60/125,
`351, both filed on Mar. 19, 1999, the disclosures of which
`are incorporated by reference herein in their entirety.
`
`FIELD OF THE INVENTION
`
`The invention relates to methods of treating mammals, for
`example humans, to reduce the occurrence of undesired
`administration reactions, to treat an LFA-1 mediated disease,
`to condition a mammal to tolerate high doses of a therapeutic
`compound and to down modulate a cell surface receptor.
`
`BACKGROUND OF THE INVENTION
`
`Administration of many therapeutic agents rapidly
`induces adverse side effects, or events, including but not
`limited to fever, headache, nausea, vomiting, breathing
`difficulties and changes in blood pressure. These adverse
`events limit the amount of a drug or therapeutic compound
`that can be given, which in turn limits the therapeutic
`effectiveness that could be achieved with higher doses of the
`drug. There is a continuing need to develop techniques
`which limit the toxicity of higher drug doses so that thera(cid:173)
`peutic efficacy can be improved. This need exists for both
`polypeptide and non-polypeptide compounds.
`Antibodies are one type of polypeptide compound for
`which there are frequently adverse events upon administra(cid:173)
`tion which limit the dose of the compound that can be
`administered. One compound associated with adverse side
`effects is the murine monoclonal antibody OKT3. OKT3
`binds to the CD3 protein complex that is associated with the
`T cell receptor (TCR) found on the surface of all T lym(cid:173)
`phocytes. Administration of OKT3 to humans rapidly
`reduces the number of circulating T cells (e.g. OKT3 is a cell
`depleting compound) and reduces the amount of cell surface
`TCR found on those T cells that remain (Cosimi, et al., 1981
`N Engl J Med, 305(6), 308-314). The immunosuppressive
`effects of OKT3 have been therapeutically useful in the
`treatment of renal transplant rejection (Goldstein & Group,
`1985 M Engl J Med, 313(6), 337-342). However, adminis(cid:173)
`tration of OKT3 induces a number of adverse side effects,
`including fever, chills, nausea, vomiting and tightness of
`chest. These side effects are believed to be caused by
`cytokine release from T cells due to OKT3-induced activa(cid:173)
`tion (Abramowicz, et al., 1989 Transplantation, 47(4),
`606-608) and complement activation (Raasveld, et al., 1993
`Kidney International, 43 1140-1149).
`Several strategies have been developed to reduce the
`OKT3-induced side effects. Anti-inflammatory steroids have
`been shown to attenuate the OKT3-induced cytokine release
`(Goldman, et al., 1989 Lancet, ii (8666), 802) (Chatenoud,
`et al., 1990 Transplantation, 49( 4), 697-702), and
`indomethacin can reduce the febrile response (First,
`Schroeder, Hariharan, Alexander, & Weiskittel, 1992 60
`Transplantation, 53 (1), 91-94). A standard 5 mg dose of
`OKT3 administered as a 2 hour infusion instead of the usual
`bolus injection was better tolerated and reduced complement
`activation, but not the cytokine release (ten Berge,
`Buysmann, van Diepen, Surachno, & Hack, 1996 Transplant
`Proc. 28 (6), 3217-3220). The adverse events induced by
`OKT3 are most significant after the first dose. While the
`
`5
`
`10
`
`2
`initial dose (typically 5 mg) induces cytokine release and
`activates complement, it also eliminates the target T cells.
`With fewer T cells and reduced TCR density on those that
`do remain, subsequent doses of OKT3 induce less cytokine
`release (Chatenoud, et al., 1989 N Engl J Med, 320 (21),
`1420-1421). One group found that after four daily doses of
`5 mg, dosing could safely be escalated to 10, 15, and 25 mg
`over the next 3 days (Woodle, et al., 1996 Clin
`Transplantation, 10, 389-395).
`Adverse events have also been associated with the initial
`administration of monoclonal antibodies directed to other
`cell surface molecules. A humanized anti-CD4 monoclonal
`antibody induced fever, chills, hypotension and chest tight(cid:173)
`ness when given intravenously to psoriasis and rheumatoid
`15 arthritis patients (Isaacs, et al., 1997 Clin Exp Immunol, 110,
`158-166). This treatment down-modulated expression of
`CD4 and caused a reduction in the number of circulating
`CD4-positive T cells, and but was not completely depleting.
`Bispecific antibodies that interact with the CD64 molecule,
`20 a receptor for the constant region of immunoglobulin (Fe
`gamma RI), and tumor associated molecules (epidermal
`growth factor receptor MDX-447, or HER2/neu MDX(cid:173)
`H210) were shown to cause flu-like symptoms such as fever
`and chills after the first dose (Curnow, 1997, Cancer Immu-
`25 nol Immunother, 45, 210-215). Similar to the effect of
`OKT3 on T cells, these antibodies caused a decrease in the
`number of circulating monocytes, which express CD64, and
`stimulated increases in plasma cytokines. A single dose of
`another monoclonal antibody directed to CD64 (MDX-33)
`30 down-modulated the expression of CD64 on monocytes and
`also caused chills, low-grade fever, headache and muscle
`aches.
`The interaction of T-lymphocytes with antigen-presenting
`cells (APCs) is one of the initial steps in the activation of an
`35 immunological response to what is perceived by the immune
`system to be a foreign antigen. Although much attention has
`been focused on the primary interaction of the T-cell recep(cid:173)
`tor with the MHC-antigen on the APC, several other cell
`surface components are also involved in T-cell activation.
`40 These ligand pairs located on the cell surface of the T-cell
`and the APC include: LFA-1/ICAM-1 (also ICAM-2 and
`ICAM-3), CD28/B7, CD2/LFA-3, CD4/MHC Class II, and
`CD8/MHC Class I. Interfering with the binding of any of
`these ligand pairs (e.g., with the use of binding molecules
`45 such as monoclonal antibodies) may decrease, inhibit, or
`discontinue the T-cell responses (de Fourgerolles et al.,
`1994, J. Exp. Med., 179:619-29; Dustin, ML et al, 1986, J
`Immunol, 137:245-54).
`LFA-1 (consisting of CDlla and CD18 subunits) inter-
`50 action with ICAM is necessary for T-cell killing, T-helper
`and B-cell responses, natural killing, and antibody(cid:173)
`dependent cytotoxicity. In addition, LFA-1/ICAM interac(cid:173)
`tions are involved in adherence of leukocytes to endothelial
`cells, fibroblasts, and epithelial cells, facilitating the migra-
`55 tion of leukocytes from the vasculature to the sites of
`inflammation (Collins, T., 1995, Science and Medicine,
`28-37; Dustin, ML. et al., 1991, Annual Rev Immunology,
`9:27-66).
`Using antibodies that interfere with LFA-1/ICAM inter(cid:173)
`actions decreases or inhibits the inflammatory process by
`blocking the activation of T-cells and/or the extravasation of
`leukocytes. In vitro, monoclonal antibodies against LFA-1
`or its ligands have inhibited T-cell activation (Kuypers, T.
`and Roos, D., 1989, Research in Immunology, 140:461-86;
`65 Springer, TA, 1987, Annual Rev Immunology, 5:223-52),
`T-cell dependent B-cell proliferation (Fischer, A et al.,
`1986, J Immunol, 136:3198-203), target cell lysis (Krensky,
`
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`
`3
`A et al., 1983, J Immunol, 131:6711-6), and adhesion of
`T-cells to vascular endothelium (Dustin, M L. et al., 1988,
`Journal of Cell Biology, 107:321-31). In mice, anti-CDlla
`antibodies have induced tolerance to protein antigens
`(Benjamin, R. et al, 1988, European Journal oflmmunology, 5
`18:1079-88; Tanaka, Y. et al., 1995, European Journal of
`Immunology, 25:1555-8), delayed the onset and reduced the
`severity of experimental autoimmune encephalomyelitis
`(Gordon, E J et al., 1995, Journal of Neuroimmunology,
`62: 153-60), inhibited lupus-associated autoantibody 10
`production, and prolonged survival of several types of tissue
`grafts (Cavazzana-Calco M S, Sarnacki S, Haddad E, et al.,
`Transplantation 1995;59(11):1576-82; Nakakura E K,
`McCabe S M, Zheng B, Shorthouse RA, et al., Transplan(cid:173)
`tation 1993;55(2):412-7; Connolly M K, Kitchens E A, 15
`Chan B, et al, Clinical Immunology and Immunopathology
`1994;72(2):198-203; He Y, Mellon J, Apte R, Niederkorn J.,
`Investigative Ophthalmology and Visual Science 1994;35
`(8):3218-25; Isobe M, Yagita H, Okumura K, Ihara A,
`Science 1992;255:1125-7; Kato Y, YamatakaA, Yagita H, et 20
`al., Ann Surg 1996;223(1):94--100; Nishihara M, Gotoh M,
`Fukuzaki T, et al., Transplantation Proceedings 1995;27(1)
`:372; Talento A, Nguyen M, Blake T, et al, Transplantation
`1993;55(2):418-22; van Dijken P J, Ghayur T, Mauch P, et
`al., Transplantation 1990;49(5):882-6). In human clinical 25
`studies, murine anti-CDlla monoclonal antibodies have
`been shown to help prevent graft failure following bone
`marrow transplantation (Cavazzana-Calco M S, Bordigoni
`P, Michel G, et al., British Journal of Haematology
`1996;93:131-8; Fischer A, Friedrich W, Fasth A, Blood 30
`1991;77(2):249-56; Stoppa AM, Maraninchi D, Blaise D,
`Viens P, et al., Transplant International 1991;4:3-7) and
`renal transplantation (Hourmant M, Le Mauff B, Le Meur Y,
`et al., Transplantation 1994;58(3):377-80; Hourmant M,
`Bedrossian J, Durand D, et al., Transplantation 1996;62(11) 35
`:1565-70; Le Mauff B, Hourmant M, Rougier J P, et al.,
`Transplantation 1991;52(2):291-6). An immunosuppressive
`drug that could reduce the incidence of both acute graft
`rejection and delayed graft function, while promoting long(cid:173)
`term survival with minimum toxicity with the potential of 40
`tolerance induction would provide major benefits to the field
`of renal transplantation.
`A need continues to exist for new methods of adminis(cid:173)
`tering therapeutic compounds which reduces side effects and
`which increases the effectiveness of the therapeutic com(cid:173)
`pound.
`
`4
`administering at least a second therapeutic dose of the
`compound, wherein the second dose is higher than the first
`dose. LFA-1 mediated disorders contemplated include
`psoriasis, asthma, rheumatoid arthritis, multiple sclerosis
`and transplant rejection. In a specific embodiment, the graft
`or transplant is a renal transplant.
`A further aspect of the invention is a method for condi(cid:173)
`tioning a mammal to tolerate high doses of a therapeutic
`compound by administering to the mammal a first condi(cid:173)
`tioning dose of a non-target cell depleting compound which
`binds to a cell surface receptor on a target mammalian cell;
`and then administering at least a second therapeutic dose of
`the compound, wherein the second dose is higher than the
`first dose.
`Another aspect of the invention is a method for down
`modulating a cell surface receptor in a mammalian cell
`population by contacting a target mammalian cell displaying
`a receptor molecule-on the surface thereof with a first dose
`of a ligand which binds to the receptor molecule and does
`not deplete the mammalian cell population; and then further
`contacting the mammalian cell population with at least a
`second dose of the ligand, wherein the second dose is higher
`than the first dose.
`The following preferred embodiments apply to all the
`above methods of the invention. In preferred embodiments,
`the therapeutic compound comprises a polypeptide which
`binds to an extracellular domain of the receptor molecule. A
`preferred polypeptide is an antibody or a fragment thereof.
`In one embodiment, the target mammalian cell is a lympho(cid:173)
`cyte such as a T lymphocyte. Non-T cell-depleting com(cid:173)
`pounds or antibodies that bind CDlla or CD18 cell surface
`receptors on a T cell, including the humanized anti-CDlla
`antibody hu1124, are specifically encompassed.
`Intravenous or subcutaneous mode of administration of
`the therapeutic compound is contemplated. In a specific
`embodiment, administration is not more than once per week.
`In an additional embodiment of each of the above methods,
`the methods further comprise administering a third thera(cid:173)
`peutic dose, wherein the third dose is higher than the second
`dose. Yet a further embodiment is the administration of a
`fourth therapeutic dose, wherein the fourth dose is higher
`than or equal to the third dose.
`Other aspects of the invention will become apparent from
`45 the following description of preferred embodiments which
`are not intended to be limiting of the invention.
`
`SUMMARY OF THE INVENTION
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`One object of the present invention is to provide an
`improved method of administering a therapeutic compound.
`This and other objects which will become apparent from the
`following description of enabling embodiments have been
`achie