il·1 L ~ nd· F 1 oo:• J1 lA457

=t ") r ,, ·.c ( ' • 1

To Build a Better Mousetrap, Use. Human Parts, M. Miller

Fil:st Monoclonal AntlOOdy to Treat Cancer Approved

Stress and Immune Respons~ After Surgical Treatment for Regional Breast Cancer, B. L Andersen, W. B. Farrar, D. Golden-Kreutz. LA. Kutz. R. MacCall m. et al. .

Estrogen Receptor Expression in Benign Breast Epithelium and Breast Cancer Risk, S. A. Khan, M. A. M. Rogers, K. K. Khurana, M. M. Meguid, P. J. Numann

Causes of Cervical Cancer in the Philippines: a Case-Control Study, C. Ngelangel, N. Munoz, · ' F. X. Bpsch, ·G. M. Limson, M. R. Festin; J. Deacon, M.Y..[acobs, M. Santamaria, et al . •

Risk Factors for Cervical Cancer in Thailand: a Case-Control Study, S. Chlchareon, R. Herrero, N. Munoz, F. X. Bosch, M. V. Jacobs, J. Deacon, M. Santamaria, et al.

Folate :{ntake, Alcohol Consumption, Cigarette Smoking, and Risk of Colorectal Adenomas, J. A. Baron, R. S. Sandler, R. W. Haile, J. S. Mandel, L A. Mott, E. R. Greenberg

Survivhl of Patients With Colorectal Carcinoma: Effect of Prior Breast Cancert R. Sankila, T. Hakulinen · .

BOOK REVIEW The Non-Hodgkln's Lymphomas, Second Edition, E. J. Seifter

CORRESPONDENCE Workshop on Hormones, Hormone Metabolism, the Environment, and Breast Cancer,_ , H. L. Bradlow, D. Davis, C. Pearson, C. Ragovin, L. Sekely, S. M. Sieber, A. Sot()<

Journa l o~ the National Cance r Institute : JNCI BI'"IL )~ ~7~nd Fl oor·s UC Sa n . ieqo · Rec e iv~d on~ 03-11 - 38

PFIZER EX. 1185 Page 1

OF

ISSN 0027-8874 Volume 90, Number 1 Pages 1-82

EDITORIAL BOARD

Barnett S. Kramer Editor-in-Chief

J. Gordon McVie European Editor

Eric J. Seifter Book Reviews Editor

J. Paul Van Nevel News Editor

Frederic J. Kaye Douglas L. Weed

Reviews Editors

Martin L. Brown Economics Editor

ASSOCIATE EDITORS

Susan G. Arbuck Frank M. Balis William J. Blot Peter M. Blumberg John D. Boice, Jr. Louise A. Brinton Bruce A. Chabner Ross C. Donehower Susan S. Ellenberg Suzanne W. Fletcher Michael A. Friedman John K. Gohagan Frank J. Gonzalez Michael M. Gottesman Peter Greenwald Donald E. Henson Susan M. Hubbard Frederic J. Kaye Hynda K. Kleinman Theodore S. Lawrence W. Marston Linehan Marc E. Lippman Scott M. Lippman

EDITORIAL ADVISORY BOARD James 0 . Arm itage 0 ystein Fodstad Bruce C. Baguley Antonio Fojo Laurence H. Baker Lori J. Goldstein William T. Beck Harvey M. Golomb Clara D. Bloomfield Elieser Gorelik Ben]amin Bonavida Jean L. Grem George J. Bosl Arnold H. Greenberg C. Norman Coleman Maureen M. Henderson 0 . Michael Colvin Gloria H. Heppner Thomas H. Corbett Ronald B. Herberman Pelayo Correa Waun Ki Hong Stephen P. Creekmore William J. Hoskins Johanna T. Dwyer Alan N. Houghton Merrill J. Egorin James N. Ingle Soldano Ferrone David H. Johnson Isaiah J. Fidler V. Craig Jordan Richard I. Fisher John S. Ko vach David FitzGerald Margaret L. Kripke

Richard D. Klausner Director, National Cancer Institute

Susan Molloy Hubbard Director, International Cancer Information Center

Julianne Chappell Chief. Scientific Publications Branch; Executive Editor

INSTITUTE

Dan L. Longo Reuben Lotan Douglas R. Lowy Susan G. Nayfield David L. Nelson Kenneth Olden Drew M. Pardoll Ross L. Prentice Alan S. Rabson Robert H. Shoemaker Richard M. Simon Michael B. Sporn Maryalice Stetler-Stevenson J. Paul Van Nevel Douglas L. Weed Noel S. Weiss

Mark G. Kris Donald W. Kufe Bernard Levin Brian R. Leyland-Jones Allen S. Lichter Guy McClung FrankL. Meyskens Anthony B. Miller Malcolm S. Mitchell James J. Mule C. Kent Osborne John J. O'Shea David M. Ota David F. Paulson Henry C. Pitot Igor B. Roninson Edward A. Sausville Thomas J. Sayers

January 7, 1998

STATISTICAL EDITORS Janet W. Andersen Jacques Benichou Donald A. Berry Barry W. Brown Bernard F. Cole Susan S. Ellenberg Scott S. Emerson Eric Feuer Laurence S. Freedman Edmund A. Gehan Barry I. Graubard Sylvan B. Green Susan G. Groshen Richard A. Olshen Philip C. Prorok Timothy R. Rebbeck Philip S. Rosenberg Harland N. Sather Daniel J. Schaid Richard M. Simon Donald M. Stablein Robert E. Tarone Sholom Wacholder

David Schottenfeld Herman A. J. Schut Richard K. Severson William R. Shapiro Roy E. Shore Paul M. Sonde! Patricia S. Steeg Herman D. Suit Sandra M. Swain Mario Sznol Raymond Taetle Ian Tannock Joel E. Tepper J. Tate Thigpen Peter R. Twentyman Larry M. Weisenthal

PFIZER EX. 1185 Page 2

EDITORIAL STAFF

Managing Editor: Janet M. Boullin

Senior Editors: Christopher L. Hatch, David I. Lewin, Richard E. Manrow, Lata S. Nerurkar

Reviews Coordinator/Book Reviews Coordinator: Elaine Price Beck

Technical Editor: Donald Baker

Senior Production Editor: Elizabeth Horowitz

Manuscript Editors: Elaine Price Beck, Joan O'Brien Rodriguez

Publication Specialist: Wayne Bittinger

Editorial Supervisor: Marla N. Banov

Editorial Assistants: Jamia V. Capehart, Winona C. Toland

Printing and Electronic Publishing Specialist/ Advertising Coordinator: Edwin A. Haugh

In This Issue Editor: David I. Lewin

Press Contact: Ellen A. Scott*

NEWS STAFF Editor: J. Paul Van Nevel

Associate Editors: Kara Smigel, Susan Jenks

Production Manager: Edwin A. Haugh

News Correspondents: Betsy Duane, Bob Kuska, Caroline McNeil, Nancy J. Nelson, Ann Saphir, Sona S. Thakkar, Dorothy A. Tisevich

Contributing Correspondents: Charles Bankhead, Elaine Blume, Peggy Eastman, Jean McCann, Judith Randal , Jan Ziegler

The Journal of the Natianal Cancer Institute is a forum for news, infonna­tion, and ideas related to cancer research, treatment, prevention, and con­trol. Accordingly, all articles and items published in the Journal are signed and, unless otherwise stated, reflect the individual views of the authors and not official points of view held by the National Cancer Institute, any other component ofthe U.S. government, Oxford University Press, or the organi­zations with which the authors are affiliated. The mention of trade names, commercial products, or organizations does not imply endorsement by the National Cancer Institute, any other component of the U.S. government, or Oxford University Press. Neither the National Cancer Institute, any other component of the U.S. government, nor Oxford University Press assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.

The Journal of the National Cancer Institute (ISSN 0027-8874) is published semimonthly and is owned by Oxford University Press, 2001 Evans Road, Cary, NC 27513.

Subscriptions

Subscriptions are available on a calendar-year basis. The annual rates (Vol­ume 89, 1997, 24 issues) are as follows. Institutions: U.S. and Canada US$150, Europe £140, rest of world US$195. Nonprofit institutions and individuals: U.S. and Canada US$120, Europe £115, rest of world US$165. Single issues are available for US$10 in the U.S., Canada, and rest of world, £7 in Europe. Personal rates apply only when payment is made by personal check or credit card. All subscription and single issue orders, changes of ad­dress, and claims for missing issues should be sent to: THE AMERICAS: Oxford University Press, Journals Subscription Department, 2001 Evans Road, Cary, NC 27513 USA. Telephone toll-free in the U.S. and Canada, 1-800-852-7323, or 919-677-0977. Fax: 919-677-1714. E-mail: jnlorders@ oup-usa.org. ELSEWHERE: Oxford University Press, Journals Subscription Department, Great Clarendon Street, Oxford OX2 6DP, UK. Telephone: +44 1865 267907. Fax: +44 1865 267485 . E-mail:jnl.orders@oup.co.uk.

Subscriptions include membership in the Information Associates Program of the International Cancer Information Center. For further information on the lAP program, call Member Services at 1-800-624-7890 in the U.S. or 301-496-7600 outside the U.S.

Permission requests, reprints, and photocopies

All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, in­cluding electronic, mechanical, photocopying, recording, or otherwise, without the express prior written pennission of the publisher (Oxford Uni­versity Press, Journals Special Sales, Great Clarendon Street, Oxford OX2 6DP, UK. Telephone: +44 I 865 267561. Fax: +44 1865 267782) or a license permitting restricted copying issues in the U.K. by the Copyright Licensing Agency Ltd. , 90 Tottenham Court Road, London WIP 9HE, or in the U.S. by the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923. Fax: 508-750-4744.

Indexing and abstracting

The Journal of the National Cancer Institute is indexed and abstracted by the following: Biological Abstracts, Cambridge Scientific Abstracts, CINAHL Information Systems, Current Awareness in Biological Sciences, Excerpta Medica, Index Medicus, Institute for Scientific Information, and Statistical Reference Index.

The Journal of the National Cancer Institute (ISSN 0027-8874) is publish­ed semimonthly by Oxford University P~ess , 2001 Evans Road, Cary, NC 27513-2009. Periodicals Postage Paid at Cary, NC, and additional mailing offices. Postmaster: Send address changes to Journal of the National Can­cer Institute, Journals Customer Service Department, Oxford University Press, 200I Evans Road, Cary, NC 27513-2009. © 1997 by Oxford University Press.

Manuscript submission

Authors submitting manuscripts (including letters to the editor) are urged to read "Information for Authors" at the back of this issue. Manuscripts will be rejected, delayed, or returned if requirements are not met. Ad­dresses for submissions: P.O. Box 3IIIO, Bethesda, MD 20824-1110; ex­press mail address: 7550 Wisconsin Ave ., Rm. 114, Bethesda, MD 20814 (telephone: 301-496-6975 ; fax: 301-402-0212).

News section

Items for the "Awards, Appointments, Announcements" column of the Ne ws, questions about previously published items, and suggestions for News stories should be sent to: J. Paul Van Nevel, JOA31 Pepper Building. 31 Center Drive MSC 2580, Bethesda, MD 20892-2580 (telephone 301-496-6631 ; fax: 301-402-4945).

Advertising

Classified advertising for cancer-related employment openings, fellowship or grant opportunities, clinical trials, or calls for scientific data to be type­set in the columns of the "Class ified Advertising" section should be submit­ted to: Advertising Coordinator, P.O. Box 31110, Bethesda, MD 20824-111 0; express mail address: 7550 Wisconsin Ave., Rm. 114, Bethesda, MD 20814 (telephone: 301-496-2621; fax: 301-402-0212). Cost quotes will be provided. Items should be typed double spaced. (See also next paragraph.) Camera­ready, boxed display ads for cancer-related employment openings, fellowship or grant opportunities, clinical trials, or calls for scientific data may be submit­ted to the Advertising Coordinator in full-, half-, third-, or sixth-page sizes. Cost quotes and size requirements will be provided. For all other advertising (e.g., for products and services), contact PRC Associates, The Annexe, Fitznells Manor, Chessington Road, Ewell, Surrey KTl7 ITF, UK (tele­phone: 44-181-786-7376; fax: 44-181-786-7262); or (U.S. inquiries only) Janet M. Boullin (telephone: 301-496-6975; fax: 301-402-0212).

Calendar of events

Information on cancer-related upcoming events (conferences, symposia, short courses, etc.) for the typeset columns of the "Calendar of Events" section should be submitted to: Calendar Editor, P.O. Box 31110, Be­thesda, MD 20824-1110; express mail address: 7550 Wisconsin Ave., Rm. 114, Bethesda, MD 20814 (telephone: 301-496-2621; fax: 301-402-021 2). This service is free of charge. Items should be typed double spaced. (See also previous paragraph.)

*Contact by telephone at212-828-3766.

PFIZER EX. 1185 Page 3

January 7, 1998 Volume 90, Number 1

1 ournal of the National Cancer Institute

CONTENTS

EDITORIALS

NEWS

ARTICLES

REPORTS

In This Issue

Is Saccharin Safe? Animal Testing Revisited, J. Zurlo. R. A. Squire 2

Psychologic Stress, Immunity, and Cancer, S. Cohen. B. S. Rabin 3

Does Estrogen Receptor Expression in Normal Breast Tissue Predict Breast Cancer Risk? 5 L. Bernstein, M. F. Press

Causes of Childhood Leukemia Beginning to Emerge, T. Reynolds

Prostate Cancer Screening Trials: Fending Off Critics to Recruit Men, C. Vanchieri

Stress Reduction: Three Trials Test Its Impact on Breast Cancer Progression, C. McNeil

Stat Bite: Age Distribution of Cancer Deaths in the United States

To Build a Better Mousetrap, Use Human Parts, M. Miller

First Monoclonal Antibody to Treat Cancer Approved

A wards, Appointments, Announcements

Long-term Feeding of Sodium Saccharin to Nonhuman Primates: Implications for Urinary Tract Cancer, S. Takayama. S. M. Sieber, R. H. Adamson, U. P. Thorgeirsson, D. W. Dalgard,

L. L. Arnold, M. Cano, S. Eklund, S. M. Cohen

Avidin Targeting of Intraperitoneal Tumor Xenografts, Z. Yew, M. Zhang, H. Sakahara. T. Saga, Y. Arana. J. Konishi

Stress and Immune Responses After Surgical Treatment for Regional Breast Cancer, B. L. Andersen, W. B. Farrar, D. Go/den- Kreutz. L.A. Kutz. R. MacCallum, eta/.

8

10

12

13

14

16

17

19

25

30

Estrogen Receptor Expression in Benign Breast Epithelium and Breast Cancer Risk, 37 S. A. Khan, M.A. M. Rogers, K. K. Khurana, M. M. Meguid, P. J. Numann

Cause!\ of Cervical Cancer in the Philippines: a Case-Control Study, C. Ngelangel, N. Munoz. 43 F. X. Bosch, G. M. Limson, M. R. Festin, J. Deacon, M. V. Jacobs, M. Santamaria, et al.

Risk Factors for Cervical Cancer in Thailand: a Case-Control Study, S. Chichareon, 50 R. Herrero. N. Muiioz, F. X. Bosch. M. V. Jacobs, J. Deacon, M. Santamaria , et al.

Folate Intake, Alcohol Consumption, Cigarette Smoking, and Risk of Colorectal Adenomas, 57 J. A. Baron, R. S. Sandler, R. W. Haile, J. S. Mandel, L. A. Molt, E. R. Greenberg

BRIEF Survival of Patients With Colorectal Carcinoma: Effect of Prior Breast Cancer, R. Scmkila. 63 COMMUNICATION T. Hakulinen

BOOK REVIEW The Non-Hodgkin's Lymphomas, Second Edition, E. J. Seifter 66

Books Received 66

CORRESPONDENCE Workshop on Hormones, Hormone Metabolism, the Environment, and Breast Cancer, 67 H. L. Bradlow, D. Davis, C. Pearso11, C. Ragovin, L. Sekely, S. M. Sieber, A. Soto

Calendar of Events • Classified Advertising 69

Information for Authors 80

• Visit the }oumal's World Wide Web site at http://www.oup.co.ukljnci/ •

PFIZER EX. 1185 Page 4

INFORMATION FOR AUTHORS

Note: The following information is updated periodically. Please refer to the most recently published version.

EDITORIAL POLICY The Journal of the National Cancer Institute

publishes manuscripts that describe new findings of particular significance in any area relating to cancer, as well as associated news items, reviews, and opinion pieces. The Journal employs a process of rigorous yet rapid review of submitted manu­scripts so that findings of high scientific and medi­cal interest can be published with minimum delay.

Review of manuscripts is conducted by the editorial board, with the assistance of external re­viewers. The editorial board initially reviews all submitted manuscripts and, whenever possible, re­turns to authors within 2 weeks all papers that are judged to be of insufficient priority for further consideration. Scientific papers of high interest will be sent out for external review. Submissions describing new results originating from the National Cancer Institute will be subject to review by individu­als outside the institute.

In most cases, authors will be notified of accep­tance, rejection, or need for revision within 8 weeks of submission. Papers sent back to authors for revision must be returned to us within the time specified in our cover letter or the manuscript will be retired from further consideration. Acceptance is contingent on author submission of complete and consistent data, accurate reference list, and conclu­sions consistent with results demonstrated in the study. Inconsistencies and inaccuracies found after acceptance may warrant return of the manuscript for resubmission. The decision to publ ish a manuscript is solely the responsibility of the editorial board. Opinions expressed by the authors are not necessar­ily those of the publisher or the editors.

If papers are accepted for publication, manu­script copy and figures will not be returned. If papers are rejected, figures-but not manuscript copy-will be returned.

The Journal endeavors to appeal to a broad, multidisciplinary audience. Accordingly , all manuscripts submitted for publication should be written with clarity and readability in mind. All manuscripts are subject to editing to ensure con­forn1ity with Journal style and editorial stand­ards. The Journal follows the precepts of the International Committee of Medical Journal Edi­tors (also known as the Vancouver Group). (See Uniform requirements for manuscripts submitted to biomedical journals. JAMA 1993;269:2282-6.)

FORMAT Articles

Articles describe new findings of major impor­tance. An Article should contain 4000 words or less, not counting abstract, Methods section, refer­ence list, tables , footnotes , and figure legends. (See "Tables and Figures.")

Reports Reports describe significant findings not re­

quiring a more extensive format. A Report should contain 2000 words or less, not counting abstract, Methods section, reference list, tables, footnotes, and figure legends. (See "Tables and Figures.")

80 INFORMATION FOR AUTHORS

Brief Comm unications Brief Communications are concise descrip­

tions of new findings of general interest. A Brief Communication should contain 750 words or less, not counting reference list, tables, footnotes; and figure legends. A Brief Communication should not be divided by heads and subheads and should not contain an abstract. (See "Tables and Figures.")

Correspondence Letters to the editor may express an opinion

about material previously published in the Journal or express views on topics of current relevance to some aspect of cancer. A letter should contain 500 words or less, not counting reference list (seven references maximum), footnotes, and figure leg­end or table. A letter relating to work published in the Journal will ordinarily be referred to the author(s) of the original item for a response, which may be published along with the letter. Complete references should be given if the letter cites the work of others; if the letter comments on an item published in the Journal, that item must be included in the numbered reference list. Letters must be submitted both as double-spaced hard copy and on disk. (See "Disks" and "Tables and Figures.")

Editorials Editorials convey opinions on any subject rele­

vant to the Journal's concerns. They may discuss the significance of a paper in the same issue of the Journal, a recent finding published elsewhere, or a particular topic of significance. Editorials are usu­ally solicited by the editors, but unsolicited sub­missions will be considered. Editorials usually contain about 1000 words, not counting reference list and footnotes, but length may be negotiated at the time of invitation.

Commenta ry Topical items under this heading convey to the

reader, in relatively nontechnical and informal style, a summary of current activities or events that bear on some aspect of cancer. Highlights of sci­enti fie meetings, the intersection of science and public policy, or news items of general interest in relation to cancer are examples of suitable subject areas . Pieces are generally solicited by the editors, but unsolicited contributions are welcome. A Com­mentary usually contains 2000-4000 words, not counting reference list, tables, footnotes , and fig­ure legends. A Commentary should not contain an abstract. (See "Tables and Figures.")

Reviews A good Review provides a comprehensive

overview of an area of cancer biology, epidemiol­ogy, prevention, treatment, or behavioral science. While Reviews should be accessible to knowledge­able readers not expert in the subject area, Reviews should be prepared with the same rigor as a re­search paper reporting specific results. (See J Nat! Cancer lnst 1997;89:6-7 for detailed guidelines on preparing reviews for this journal. A copy of the guidelines can be obtained by contacting the Jour­nal Office, P.O. Box 31110, Bethesda, MD 20824-1110; telephone: 301-496-6975; fax: 301-402-0212.) While most Reviews are solicited by the editors, unsolicited submissions are also welcome. A Re­view should contain 6000 words or less, not count­ing abstract, reference list, tables, footnotes , and figure legends. (See "Tables and Figures.")

Book Reviews Book Reviews are solicited by the book review

editor and contain I 000 words or less.

SPECIFIC INSTRUCTIONS Submission of Manuscripts, Including Letters to the Editor

New submissions of Articles, Reports, and Brief Communications originating in Europe (those whose corresponding authors have European addresses) should be sent to: Prof. J. Gordon Me Vie, European Editor of the Journal of the National Cancer Insti­tute, Cancer Research Campaign, 10 Cambridge Terrace, London NWI 4JL, UK. Articles, Reports, and Brief Communications from other areas and all Editorials, Commentary, Reviews, and letters to the editor (Correspondence) should be submitted to: Editor-in-Chief, Journal of the National Cancer In­stitute, P.O. Box31110, Bethesda, MD 20824-1110 (telephone: 301-496-6975); express mail address: 7550 Wiscons in Ave., Rm. 114, Bethesda, MD 20814. All revised manuscripts should be sent to the Editor-in-Chief, at Bethesda.

Manuscript title page, the body of the manu­script, reference list, footnotes, and figure legends must be typed double-spaced; allow sufficient space between lines of type so each page contains no more than 26 lines (plus page number). Tables may be single- or double-spaced, but the type must be large enough and the lines of type sufficiently well spaced to be easily read. Send an original and three copies of the manuscript. Do not staple figures to the manu­script. Four clear, can1era-ready (reproducible) sets of all illustrations must be provided; do not send photocopies of photographs, photomicrographs, gels, blots, or sin1ilar material. The cover leiter for the manuscript must conform to requirements stated in the "Cover Letter" section below. Manuscript submissions not meeting these requirements (i.e., cover feller statements, number of clear copies of illustrations, number of manuscript copies, and spacing in hard copy of manuscript} will be returned to the author without review.

Letters to the editor and solicited manuscripts must be submitted initially both as double-spaced hard copy and on disk. (Authors of other types of manuscripts will be asked to provide disk copies at time of acceptance.)

Keep a copy of your manuscript.

Disks Manuscripts on disk should be in Microsoft

Word for PC with all formatting codes removed, except for paragraph indentations. Do not send manuscript sections (e.g., title page, references, and tables) as separate files. Do not send figures on disk. Write the first author's name on the disk label, along with the name and version of the program used to create the fil e. Please virus check the disk and verify that it contains the correct file .

Express Mail Decision Letter Authors wishing to receive as rapid a response

as possible should include a pre-paid, self-ad­dressed express mail envelope with their submis­sion. 1 f no pre-paid envelope is included, or if the express mail carrier refuses our pickup request, the decision letter will be sent by first-class mail through our mail room.

Title Page The title should be brief(14 words or less) and ,

except for Editorials and Correspondence, should not be in sentence form. If a letter to the editor pertains to an item published in the Journal , the title of the original item should be the title of the letter, preceded by "Re:." The title page should give the full name and affiliation of each author and the name and address of the single author to whom correspondence and/or reprint requests are to be sent.

Journal of the National Cancer Institute, Vol. 90. No. I , January 7, 1998

PFIZER EX. 1185 Page 5

Please include the telephone and fax numbers and e-mail address of the corresponding author. Authors should be aware that the individual named first in a list of authors of the paper, and his/her institutional afliliation, wi ll be the one named in any pub! ication-related or post -pub! ication citation or com­munications by the Journal concerning the paper.

Abbreviations Journal policy is to avoid the use of abbrevia­

tions whenever possible. If abbreviations are es­senti al, list and define them. Author-created abbreviations are not to be used.

Key Words List up to four key words for index purposes.

Abstract An Article, Report, or Review must contain an

abstract. Abstracts should be written using com­plete sentences and must not exceed 250 words. An abstract should clearly state unique elements of the work, should be readable by nonspecialists as well as experts in the particular field, and should con­cisely state all important findings of the study. All information in the abstract (including implica­tions) must be explicitly stated in the text.

Include, as appropriate, the fo llowing headings in abstracts for Articles and Reports only: Back­ground, Mel/rods, ReSIIIIs, and Conclusion{s). The Backgrowrd should come from the Introduction of the paper and should note relevant previous find­ings, designated as those of the authors and/or other investigators. It should also state the purpose of the present paper. The Me/hods should indicate all important materials or techniques used to fulfill the purpose of the study; these methods will be de­scribed more fully in the Methods section of the paper; for each finding noted in the Resulls, a corresponding method should be provided in the Me/hods. The Resulls should contain only informa­tion detailed in the Results seclion of the paper. All importanl significant results should be noled in the Resulls. The word "significant" should be used only if a result is statistically significant, and a P value or confidence interval should be cired in the abstract (as in the text) for any sratistically signifi­cant finding.ll1e Me/hods must not conrain results, and the Resulls must not contain methods. The next section of the absrract should state any important Conclusion{s) demonstrated or suggested by the results. The Conclusion{s) should come from the Discussion section and can include any implica­tion(s) derived as a nexl logical step or inference directly from the results of the study reported and olher related findings from investigators men­tioned in the Discussion. lmplication(s), as stated in the Discussion, may suggest directions for fulure experimenral research and/or possible clinical ap­plications and may note a particular need for con­fi rmatory srudies or oiTcr cautions regarding interpretation of the results.

Authors should carefully review each stale· ment in the abstract to ensure that the above points are satisfied.

Text All submitted text should be typed double­

spaced and should be written in srandard gram­matical English. (Refer to the AMA Manual of S1yle or a recent issue of the Journal on questions of style.) lndenl the first line of each paragraph. Number all pages consecutively. Dot-matrix or italicized text will not be accepted. All symbols and abbreviations should be defined. Number refer­ences, tables, and figures in the order in which they are cited in the text. References in tables should continue the sequence of numbers in the tcxl at the

point where the table is first mentioned (i.e., num­bering of table references should not be reserved until the end of the reference list).

Gene No menclature ·n1e Journal does nor italicize symbols desig­

nating genes, alleles, or loci. (Authors should fol ­low such symbols with wording that clarifies the meaning of the symbol.) It has become difficult to consistently apply the system of ilalicizing these symbols 10 distinguish them from phenotype, es­pecially since author usage is often inconsisrent. In addition, interpretations of proper use of italics vary, and incorrect use can be misleading.

Journal policy is to allow use of the specific gene symbol preferred by the author. For human genes, if a symbol other than that listed in Human Gene Map­ping is preferred, the author should identi fy paren­thetically, al lirsl mention, lhe appropriate gene symbol lisred in the Human Gene Mapping report from the most recent international workshop on hu­man gene mapping. All Human Gene Mapping des­ignations for human genes should be capitalized; for other species, the symbols should be lowercased and the species of origin should be identified at first mention. Proteins arc distinguished from genes by encoding for them by an initial capital (e.g., Nm23).

Sequence Informa tion Before final acceptance of any manuscripl con­

tain ing new nucleotide and/or amino acid se­quences, the author(s) must deposit the sequence information with the GenBank database (National Center for Biotechnology Information, Bldg. 38A, Rm. &N-803, 8600 Rockville Pike, Bethesda, MD 20894; telephone: 30 1-496-2475 ; fax: 301 -480-9241 ; e -m ail for information: info@ncbi.nlm.nih.gov; e-mail for submission: gb­sub@ncbi.nlm.nih.gov). Alternatively, authors of manuscripts originaling from outside the United Slalcs may submit sequence in formation to either the European Molecular Biology Laboratory (EMBL) database (European Bioinformatics lnstitule, Hinx· ton Genome Campus, Hinxton Hall, Hinxton, Can1bridge CB I 0 IRQ, UK; telephone: 44-1223-494400; e-mail: datasubs@ebi.ac.uk) or the DNA Databank of Japan database (National Institute of Genetics, Mishima, Shizuoka 411 , Japan; telephone: 81-55 1-75-077 1; e-mail: datasub@ddbj.nig.ae.jp). The accession number(s) must be provided to the Journal to verify that the infom1ation has been de­posited in one of the three databases. Accession number(s) will be published in the relevant fig­ure legend(s).

Methods The description in the text of methods used

must be succinct but sufficiently derailed to allow replication of the study by a qualified investigator. The Methods sections of Articles and Reports arc exempted from the word count (see "Articles" and "Reports," above). Authors should specify full names, rypes, amounts, and sources of reagents (giving complete names and locations of suppli­ers); full names as well as standard abbreviations of labeled compounds and isotopes used for label­ing; concentrations of solutions; and reaction con­ditions (e.g., incubation limes and temperatures). In addition, techniques and procedures used should be accurately named, clearly and thoroughly ex­plained, referenced when appropriate, and or­ganized under appropriate subheadings. The Methods section must be complete and should include the merhodology corresponding to each of the end points presented in the Results. Authors should specify experimental conditions that limit the generalizability of the Results.

Journal of the National Cancer Insti tute, Vol. 90, No. I. January 7. 1998

For clinical trials, authors should clearly define and explain the purpose of the study, study design, numbers of patients, cl inical staging of disease, type and sequence of treatments given before and during study, lime points for evaluation of re­sponse, duration of follow-up, end points used (e.g., overall survival, disease-free survival), spe­ci fic outcomes assessed, and methods of assess­ment. This requirement should be met, even when the major focus of a study is not the clinical trial to which it is related (e.g., association of gene, mes­senger RNA, or protein expression with disease therapy or prognosis). (See "Clinical Trials.")

'The methods of statistical analysis should be described in sufficient detail that a knowledgeable reader could reproduce the analysis if the data were available. All tests of statistical significance must be two sided, and the abstract and text should so state.

Reference List For reference citation, the Journal follows the

style guidelines of the International Committee of Medical Journal Editors (also known as the Vancou­ver Group). The reference list should be typed dou­ble-spaced. Number references in the order in which they are cited in the text. Use Index Medicus abbre­viations of periodical names. For each periodical article, provide author(s), Iitle, journal, year, volume, and first and last page numbers; if an article has more than six authors, list the first six only and add "et al." For a book chapter or section, give the author(s) and title of the pertinent part, the name(s) of book edi­tor(s), the book title, location and name of publisher, year, and page numbers. Examples:

Standard journal article {I) Pezzino G, Remington PL, Anderson HA,

Harms L, Phillips JL, Bruskewitz R, et al. Trends in the surgical treatment of prostate cancer in Wisconsin, 1989-1991. J Nat! Cancer Inst 1994;86: 1083-6.

Book (2) De Vila VT Jr, 1-lellman S, Rosenberg SA,

editors. Cancer: principles and practice of oncol­ogy. Vol2. 4th ed. Philadelphia: Lippincott, 1993.

Chapter in book (3} Norton JA, Levin B, Jensen RT. Cancer of

the endocrine system. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Vol 2. 4th ed. Philadelphia: Lippincolt, 1993:1333- 1435.

Papers still "in press" also may be listed. How­ever, citation of papers in preparation or submilted for publication, unpublished observations, and personal communications should be noted paren­thetically in the texl, not in the reference list; in each case, cite the names of the first six investigators only and add "et al." Permission must be obtained in wriling from one author of papers still in press, in preparation, or submitted for publica! ion, unpub­lished data, and personal communications.

Tables and F igures Manuscripts may contain a speci fic, limited

number of tables and figures. Each panel of a figure will be counted as a separate illustration, unless the panels represenl a logical sequence of closely re­I a led items; dissimilar panels should nol be grouped together (e.g., a graph and a photo) unless they present the same data in different forms (e.g., quantitative and qualitative displays). The maxi­mum numbers of tables plus figures are as follows: Articles and Reviews (eight}; Reports and Com­mentary (four); Brief Communications (two); Cor­respondence (one). After manuscripts have been accepted pending revision, they will not be further processed unless these requirements are mel.

INFORMATION FOR AUTHORS 81

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Tables may, be single- or double-spaced, but the type must be large enough and the Jines of type sufficiently well spaced to be easily read. Com­puter printouts are acceptable. Provide table titles, footnotes (as appropriate), and headings for all columns. Indicate units of measurement used and define all abbreviations.

Four sets of all illustrations must be provided ; each illustration should be clear and reproduc­ible-that is, every copy of each illustration should be appropriate for scientific review and acceptable as camera-ready for publication. Do not send pho­tocopies of photographs, photomicrographs, gels, blots, or similar material; do not send black-and­white photocopies of color originals; do not send negatives; do not send figures on disk; do not staple or clip figures to the manuscript. The type and symbols in figures should be easily readable when the fi gure is reduced for publication. Artwork should be drawn or printed in black ink for good reproduction; color illustrations and photos \viii be considered only if they are essential and black­and-white wi ll not suffice. Printouts of computer­generated illustrations are acceptable; glossy photographs of printouts are not required. A void very small type in figures. Type figure legends double-spaced and, if possible, all on one separate sheet; identify in each legend any lettering or sym­bols in the figure. Use the back of the illustration to indicate the figure number and the top edge of each; make sure that writing on the back of one figure does not transfer to the front of another. Label separate figure parts with capital letters (e.g., "A" and "B").

Cover Letter A cover letter signed by the corresponding

author should accompany all submitted manu­scripts, including letters to the editor, and must include the information in the following six state­ments:

1) All authors of this research paper have directly participated in the planning, execwion, or analysis of the study m: all authors of this nonre­search paper have participated in its drafting.

2) All authors of this paper have read and approved the final version submilled.

3) The contents of this manuscript have not been copyrighted or published previous~y. (But see "Pennission to Reproduce Tables or Illustrations.")

4) The contents of this manuscript are not now under consideration/or publication elsewhere.

5) The contents of this manuscript will not be copyrighted, submitled, or published elsewhere while acceptance by the Journal is under consid­eration.

6) All related manuscripts, published or unpub­lished, by one or more authors of this paper have been included with the manuscript submission m: there are no related manuscripts, published or un­published, by any author(s) of this paper.

All manuscripts are considered for publication with the clear understanding that their contents have not been previously published, but abstracts and papers presented at scientific meetings and published as part of the proceedings are excepted. Failure to submit related abstracts and manuscripts will be cause for rejection, even if the failure is discovered after an acceptance letter is mailed.

The Journal strongly discourages authors from the practice of fragmented reporting of aspects of a single investigation. Authors submitting a paper that is but one of a number of existing or pl anned manuscripts related to a single study must include a statement in the cover letter that (a) so identifies the paper and (b) justifies the use of the fragmented

82 INFORMATION FOR AUTHORS

approach. Authors must describe in the cover letter the scope of each planned related paper. The sub­mitted paper itself must clearly explain and justi fY the fragmented approach and reveal the full extent of the investigation .

Written penniss ion from the following parties should be submitted with the cover letter, as appro­priate: (a) those named in acknowledgements who have been credited with substantive scienti fic contri­butions to the work and (b) one author of each work cited in the manuscript as a personal conununication, unpublished data, or a manuscript in preparation, sub­mitted for publication, or in press.

If an author has been sanctioned by the Office of Research Integrity of the U.S. Public Health Service, the manuscript will be returned unless the cover letter afiirrns that the research described is unrelated to the matter for which the author was sanctioned.

Conflict of Interest Journal policy requires that all authors of re­

search papers, Reviews, Commentary, Editorials, and Correspondence sign a statement when copy­ri ght fonns are signed revealing 1) any financial interest in or arrangement with a company whose product was used in a study or is referred to in a Review, opinion piece, or letter, 2) any financial interest in or arrangement with a competing com­pany, and 3) any other financial cmmections, direct or indirect, or other situations that might raise the question of bias in the work reported or the conclu­sions, implications, or opinions stated-including pertinent commercial or other sources of funding for the individual author(s) or lor the associated depart­ment(s) or organization(s), personal relationships, or direct academic competition. If the manuscript is published, such infonnation may be communicated in a note following the text and references.

Copyright It is a condition of publication that authors

assign copyright to Oxford University Press. This ensures that requests from third parties to repro­duce papers are handled efficiently and consis­tently and will also allow the material to be as widely disseminated as possible. Fonns for this purpose will be sent to authors when manuscripts are solicited and when unsolicited manuscripts have been accepted for publication. Authors may use their own material in other publications, pro­vided that the Journal is acknowledged as the origi­nal place of publication and that Oxford University Press is notified in advance in writing.

Permission to Reproduce Tables or Illustrations

If tables or illustrations have been published previously, authors submitti ng a manuscript to the Journal must obtain written pem1ission from the copyright holder (usually the periodical in which they appeared) before the Journal will reprint the material. If a table or illustration is modified, permis­sion to use an adapted version is required. Notice to the author of the original manuscript is encouraged.

Consent and Approval Manuscripts reporting on biomedical studies

involving human subjects must include explicit assurance that written infonned consent was ob­tained from each subject or from his or her guard­ian. Such manuscripts must include a statement that the human investigations were perforrned after approval by a local institutional review board and in accord with an assurance filed with and ap­proved by the U.S. Department of Health and Human Services, where appropriate.

Animal Welfare Any study involving experiments with animals

must state that their care was in accord with insti­tution guidelines. Where applicable, the dose and schedule of anesthetics and analgesics should be reported .

Clinical Trials* When reporting clinical trial s, authors should

discuss briefly the quality-control methods used to ensure that thei r data are complete and accurate. A reliable procedure should be cited for ensuring that all patients entered in the study are actually re­ported on. If no such procedure is in place, its absence should be noted. Any procedure employed to ensure that assessment of major end points is reliable should be mentioned (e.g., second-party review of responses) or the absence noted.

All patients registered in the study should be accounted for. The report should specify for each treatment the number of patients who were not eligible, who died, or who withdrew from treat­ment. The distribution of follow-up times should be described for each treatment, and the number of patients lost to fo llow-up should be given.

The assessability rates for major end points must be at least 85%. Not more than 15% of eligible patients should be lost to foll ow-up or considered not assessable for response owing to early death, protocol violation, missing inforn1ation, or other reason.

In randomized studies, the report should in­clude a comparison of survival and/or other major end points for all eligible patients as randomly assigned- that is, with no exclusions other than those not meeting eligibility criteria.

The sample size should be sufficient to either establish or conclusively rule out the existence of effects of clinically meaningful magnitude. For "negative" results in therapeutic compari sons, the adequacy of samp le size should be demon­strated by either presenting confidence limits for true treatment differences or calculating statistical power for detecting differences. For uncontrolled phase 11 studies, a procedure should be in place to prevent the accrual of an inappropriately large number of patients when the study has shown the agent to be inactive.

Authors should state whether there was an in­itial target sample size and, if so, what it was. They also should specify how frequently interim analy­ses were perforrned and how the decisions to stop accrual and report results were arrived at.

All claims of therapeutic efficacy should be based on explicit comparison with a specific con­trol group, except in special circumstances where each patient is his or her own control. If nonran­domized control subjects are used, their charac­ter ist ics should be presented in detail and compared with those of the experimental group. Potential sources of bias should be adequately di s­cussed. Comparison of survival between respond­ers and nonresponders does not establish efficacy and should not generally be included. Reports of phase 11 trials that draw conclusions about antitu­mor activity, but not therapeutic efficacy, generally do not require a control group.

The patients studied should be adequately de­scribed. Applicability of conclusions to other pa­tients should be carefully dealt with. Claims of subset-specific treatment differences must be care­fully documented statistically as more than the random results of multiple subset analyses.

• Adapted from: Methodologic guidelines for re­ports of clinical trials. Cancer Treat Rep 1985;69: 1-3.

Journal of the National Cancer Institute. Vol. 90, No. 1, January 7, 1998

.J

PFIZER EX. 1185 Page 7

progression is under way at Stanford where Spiegel and colleagues are repli­cating the earlier study with a larger group. Initiated in 1990, the trial has 125 participants who were randomized into two groups, one of which attended support sessions.

Now about three-quarters of the way through a I 0-year followup, the investi­gators are monitoring endocrine and cellular markers of immune function, such as cortisol levels and natural killer cell activity, as well as recurrence and survival rates. Spiegel said they expect to have some preliminary resu lts pub­lished later this year, and final results, including survival data, could be ready around the year 2000.

A third trial on stress reduction and cancer progression is taking place in Canada at seven different si tes. Led by Pamela Goodwin, M.D. at Mount Sinai Hospital , Toronto, the trial is replicating Speigel 's intervention with 235 women. Goodwin said this study should have completed recruitment by the end of 1997 and that results, in­cluding survival data, could be avail­able around 2000.

Controversy Continues

A major hypothesis in all three studies- that stress reduction can alter immune function in a way that influences cancer progression - is a controversial one, said Sheldon Cohen, Ph.D. and Bruce Rabin, M.D. , University of Pittsburgh, in their edi­torial on page _. There is too little known, for one thing, about the type and magnitude of the immune re­sponses that influence cancer progres­sion, they say.

Another problem in studying the role of psychosocial interventions are the number and complexity of factors that

14 NEWS

might independently influence immune responses and cancer progression. All th ree trials now in progress are control­ling for known prognostic factors, such as the extent oflymph node involvement and whether the tumor cells had estro­gen receptors. But numerous other fac­tors could play a role, including the immunosuppressive effects of cancer treatment, the details of which are not completely known.

Another point noted by Cohen and Rabin - and one that turns up repeat­edly in the literature on stress reduction and cancer survival - is that a support group could influence disease progres­sion by means other than the stress reduction/immune response mechanism. For instance, supportive interventions might work because they encourage treatment compliance.

Spiegel said that he and colleagues examined this issue in their earlier study by reviewing participants' medical records. They found no difference in treatment that could account for the difference in survival rates. For that trial , "we've pretty much ruled out dif­ferences in treatment as an explanation," he said.

However, the impact of interven­tion on compliance with treatment is still an unknown. One hypothesis be­ing tested in the Canadian study, said Goodwin, is that the psychosocial intervention improves survival by encouraging compliance. The Ohio State researchers arc also looking at medical treatment, collecting data not only on prescribed treatment but also on the chemotherapy doses that each patient actually receives.

It is a key issue, Andersen said. "This is something we are looking at very closely."

- Caroline McNeil

To Build a Better Mousetrap, Use Human Parts

Historically disappointing results wi th mouse-based monoclonal antibod­ies (MAbs) have biased many clinicians against th is approach to treating human diseases. ow, re-engineered antibodies are ready for a comeback, thanks to the persistence of a few researchers who were unwilling to abandon the idea.

One MAb, IDEC-C2B8 or rituximab, recently was approved by the Food and Drug Admini stration for treatment of a type ofnon-Hodgkin's lymphoma (see sidebar). Several others, such as HER2 for breast cancer and A33 and anti­EGP40 for colorectal cancer are in clinical trials. And at least two dozen other MAbs are in various stages of clinical testing in the cancer setting.

Such signs of progress have re­kindled hope in those researchers who

have contin­ued over the past several decades to explore the basic MAb concept ­that an anti­body injected into a cancer patient could

Dr. Thomas A. Waldmann seek out a specific anti­

gen on cancer cells, bind to that antigen, and activate the body's immune system to kill with great specificity only the cancer cells.

The breakthrough that turned that vision into clinical reality, according to Thomas A. Waldmann, M.D., chief of the metabolism branch at the National Cancer

Journal ofthe National Cancer Institute, Vol. 90, No. I, January 7, 1998

PFIZER EX. 1185 Page 8

··· ·· ······························ ·· ··········

Institute, was the development of genetic engineering teclmiques in the early 1980s. The ability to genetically engineer anti­bodies "was a quantum leap in immune intervention," he said, allowing research­ers for the first time to combine the bind­ing sites from mouse antibodies with human antibody elements.

The resulting chimeric Mab would. retain not only the high binding affinity of the murine antibody, researchers hypothesized, but gain the therapeutic advantages of a human antibody: a bet­ter immune response targeted at cancer cells, a reduced immune reaction to the mouse antibody, and a longer half life.

Al though the creation of chimeric antibodies diminished considerably the human anti-mouse antibody response, Greg Winter, Ph.D, and colleagues from the Medical Research Council Labora­tory of Molecular Biology of Cam­bridge, England, went a step further in the mid-1980s. They succeeded in gen­erating humanized antibodies that re­tained only the specific binding regions of the parent rodent MAb, rather than entire variable domains.

This step was even further refined and improved by researchers at Protein Design Labs, Inc., Mountain View, Calif. , which received a fundamental U.S. patent covering most humanized monoclonal antibodies in late 1996.

A Productive Cell Line

However, before any compound, protein, or other subtance can be con­sidered for development as a therapeutic drug, a large-scale manufacturing tech­nique must be devised. According to Mitchell E. Reff, Ph.D. , senior director of molecular biology at !DEC Pharma­ceuticals, San Diego, it wasn't enough to genetically engineer the murine pre-

cursor to rituximab, which was isolated by Darrell Anderson, Ph.D., in 1990.

"When I started at !DEC, it cost about $ 10,000 per gram to make an antibody," explained Reff. "Even if a drug works very well, if it costs that much to manufacture, you don't have a product."

In 1991 , Reff and a team of other experts in genetic engineering of mam­malian cells, reduced the cost of making C2B8, which was created by !DEC Pharmaceuticals and developed in col­laboration with Genetech, Inc. (San Francisco), F. Hoffman La-Roche Ltd. (Switzerland), and Zenyaku Kogyo Co., Ltd (Japan).

Although ritux imab is a chimeric rather than a humanized antibody, it has not been associated with a significant immunogenic response in clinical trials

Or. Mitchell E. Reff and Dr. Darrell Anderson

for non-Hodgkin 's lymphoma. " In this particular indication, patients are [al­ready] immunosuppressed," Reff ob­served. "The important part of the chi­mera here may not be that the body won't mount an antibody response; rather, it may be the effector function that the human portion of the antibody brings to it - the ability to ki ll a cell."

He also pointed out that non-Hodgkin 's B-celllymphoma is an accessible tumor. "Antibodies are big molecules; it 's easier for them to effectively get to the tumor

Journal of the National Cancer Institute, Vol. 90, No. I, January 7, 1998

in lymphoma or leukemia than in solid tumors."

In addition to two ki lling mechanisms hypothesized for the C2B8 antibody, which involve both the complement system and killer cells, a third mecha­nism has been recently proposed. With the antibody attached to its surface, a tumor cell may become sensitive to apoptotic signals, particularly in the presence of chemotherapy drugs.

" Did we select this antibody 7 years ago because we thought it might be apoptotic?" Reff said. "No, this is what I call luck ... that wasn't planned, but it works out well."

HER2 Antibody

When Paul J. Carter, Ph.D., senior scientist in the Department of Molecular Oncology at Genentech, Inc., arrived at the company in the late 1980s, he was only peripherally aware of its mono­clonal antibody program, which included a murine antibody, 4D5, to the HER2 cell-surface receptor.

evertheless, he soon learned that while investigators, such as Dennis Slamon, M.D., Ph.D., of the University of California, Los Angeles, were plan­ning to begin testing the murine 4D5 in the clinic, work on humanization of the antibody was al ready well under way. When 3 of 8 patients treated with 40 5 developed an adverse immune response, Carter became convinced that a human­ized antibody was the way to go.

"It just seemed very perverse and retrogressive to use mouse antibody in the clinic," Carter recalled. "I became quite vocal about the need to make a humanized version of the HER2 anti­body."

Without an official corporate go­ahead, Carter and Len Presta, Ph.D., a molecular modeler at Genentech Inc., started engineering an antibody based on

NEWS 15

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Winter's description and an in­dustry paper. Phase Il l trials with the humanized HER2 an­tibody are nearing completion; results should be available in 6 to I 8 months.

Primatizcd Antibodies

Asked why he continued to bel ieve in the promise of mono­clonal antibodies, Laurence J Korn, Ph.D., chief executive officer of Protein Design Labs, explained that although early

ing human antibodies, he explained, and are likely to dominate the development of the next generation of thera­peutic antibodies. Kom, too, has high hopes for human antibodies, which, he pointed out, can be constructed to targets such as vi ruses.

studies were not as successful Engineered chimeric a ntibodies fo r cancer therapy.

One of the most exciting elements of the original "magic bullet" concept was that MAbs might function not only to alert the immune system to an in­vader but to actually deli ver a fatal strike. Many researchers

have not abandoned this notion. In the future, Carter predicted, '"we' ll see dif­ferent ways of arming antibodies with something potent, such as a radionuclide or something else that packs a punch when the antibody gets to the target."

as hoped, they confirmed "the Courtesy Gcnetech, Inc.

tremendous target specificity of mono- tion, which results in the production of clonal ant ibodies" as well as their thera- PRIMATIZED® antibodies. peutic potential. Although PRIMATIZED® antibodies

If humanization produces an anti- may have clinical value, according to body that is 90% human, one might Carter, humanization wi ll soon be super-assume that the next logical step would ceded by far more rapid, direct routes to be to synthesize a product that is I 00% human antibodies. Antibody phage human. Because humans cannot be libraries are the fastest route to obtain- - Margie Miller

injected, however, with a disease-bear-ing agent in order to make antibodies, and because the human body does not produce antibodies to the natural proteins that researchers most wish to target (i.e., those involved in autoimmune and in­flammatory diseases, and cancer), ex­periments at IDEC have taken a differ­ent tum.

"We thought that if a mouse-human chimera is close to human," Relf said, "maybe a nonhuman primate-chimera would be just like human." Using this line of reasoning, Roland Neuman, Ph.D.,

abil HarUla, Ph.D., and colleagues at IDEC found that by putting a human antigen, such as CD4, into a monkey they could create a high-affinity antibody to human CD4, as well as to other human antigens. "It's almost indistinguishable from a human antibody," Relf said. Four separate U.S patents have been allowed to !DEC for primate-human chimeriza-

16 NEWS

First Monoclonal Antibody to Treat Cancer Approved

On ov. 26, the U.S. Food and Drug Administration approved the first biotechnol­ogy product developed to treat patients with cancer - a monoclonal antibody for one type oflymphoma.

Rituximab (trade name Rituxan) has been approved to treat patients wi th low-grade B-cell non-Hodgkin's lymphoma who have not responded to standard treatments. The product was developed by !DEC Pham1aceuticals Corp., San Diego, and Genetech, Inc., San Francisco.

Patients with 8-cell lymphomas often achieve remission wi th initial therapies but have multiple recurrences and relapses over the course of their disease, which is ulti­mately incurable. Rituximab targets and destroys the 8 -cells involved in the disease with less severe side-effects that other treatments.

Lead Deputy FDA Commissioner Michael A. Friedman, M.D., said that it took "decades of basic scientific research" to get monoclonal antibodies from the labora­tory to a marketable product. "Although not yet the magic bullet we are looking for, it will give patients and their physicians another less toxic treatment option when other treatments fail," he said.

Journal of the National Cancer Institute. Vol. 90, o. I, January 7, 199l\

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