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1 THF COUNCIL FOR TOBACCO RESRARCK-U.S.A., INC. (8M APPLICATION NO. 1054R1 MOoNArmtM HKOIJ2047374 T0: The project committee ccsrpriaing Dra. Bing, Jacobson and Sonmders SiIDJACT: Herbert McKennis, Jr., Ph.D., Medical College of VirginiaA Richmond, First renewal application No. 1054R1 "Studies aimed at development of immuno-assays for hicotine and nicotine metabolites" HISTORY CTR grants for study of Enzymatic Transformations of Nicotine and Itelated Cam ounds at the Medical College of Virginia began in 1956 th an appropriation of $29,080 to Drs. Larson, Aaag and MeKtnnis followed byy tvdro renewals in the following years. Then, with McKennis as Principal InveRtigator, ten more annual grants were made for continuing,the work through 1968. During this period, which began in a practically virgin field, a great deal of progress was made in describing the pathways of nicotine metabolism and in isolating,'identifying, and characterizing the intermediates. This group became the acknowledged world authority on nicotine metabolism. Fron 1964 into 1972, the enterprise received supp?ementary, and then full support (under several titles) fran the American Medical Association's Educational and Research Foundation. C.T.R. grants were suspended. When the AMAIIiF was terminated, C.T.R. made a grant of $b0,000 to McKennis (#868) for study of the Biological Activit of Tobacco Smoke Com nents and A71ied_ Substances. (October 1, 1972 By this time, the Board and Staff of C.T.R. felt that further elaboration of the metabolic processes should be deferred in fa%ror of increased efforts to appl.,y the accumulated information to specific problems of practical importance. An application for renes,ra7l of Grant # 868 was therefore denied, though supplements were made for phase-out and termination. EXtensive conversations were held with Dr. McKennis in an effort to interest him and his team in a rather drastic change of direction. A new application (#970, January 1, 1974) for study of the Pharmaeodynamics of Cotinine came closer to the mark but was denied as still non-competive in terms of C.T.R. needs at the time. Another, #1029, submitted as of May 1, 1975 met the same fate. Meanwhile, Dr. McKennis had held his experienced staff together by extremely economical use of residual funds f7om the A.M.A.E.R.F. grant that extended to about May 1974, in addition to the CTR grants. THE: CIIIiRENT FROJDCT ,#1054 Va. At this point it became quite apparent that Dr. Castro's project for producing a radioinnnuno assay for nicotine could benefit by the assistance

arant Application No. 10;4R1 , NK~.~2047375 2. of skilled organic chemists for the preparation and characterization of nicotine derivatives suitable for combination with proteins and use as antigens to raise antibodies that might have affinity for nicotine. Beyond this was the problem of preparing analooous derivatives of prinicpal nicotine metabolites, especially cotinine, and others such as metanicotine and k-0-pyridyl)-b- methylamino-butyric acid. By this plan, Castro would be freed to concentrate upon the production of antibodies andd development of assay techniques. A counter proposal was therefore made to Dr. MeKennis along these lines, which he accepted (November 21, 1975). No elaborate protocol or budget plan was written. Rather it was understood that priorities would be eet up and progress assessed through coinferences as the work proceeded. Since he had asked for $40,396 for his application #1029, which was denied, we aLtocated $45,000 for the eleven month period from December 1, 1975 to Noirember 30, 1976, to see how things vtnuld go. REPORTS Verbal and letter reports were made at intervals and a summary report was rendered as of June 25, 1976. This is attached. I have found it encouraging. Not only does it show good progress in making protein- nicotine adducts by repetitions of processes recorded in the literature, but also by new chemistry aimed at synthesis of protein adducts with nicotine metabolites. There are indications that McKennis' interest has really been aroused in this work. His studies of cotinine retention and elimination, carried out eoncurrently, andreported in ea manuscript, seem to emphasize the dynamics and 'kiaetics in a manner relevant to main goals as we see them. It appears that our experiment in bringing about a reorientation may have succeeded. Mean- while, a number of pepers have appeared as products of the earlier grants. The grant was made without commitrnent beyond one year because of uncertainty as to how productive it would be. Now continuation appears highly desirable (See Castro's reports on #S8$). FINAWIA.L Meanwhile, Dr. McKennis points out that all funds remaining from A.Mr.A.E.R.F. have run out. Since our #].054 did not begin at the time projected for #1029 (denied), he Pxhausted our $45,000 appropriation by August 1, 1976. In his letter of July 3, 1976, he requested a $20,000 supplement to carry him to November 30, 1976, the end of the eleven-month period completed. As an alternative, I suggested a $10,000 interim appropriation for the interval to October 1, 1976, and submission of a new application for Year II beginning on that date. Under this plan the proposal could be neviewed by the project committee and also presented to the full Board this month if deemed necessary.

Grant Application No. 1054Ii1 3. HK02047376 - RENEWAL APPLICATION Dr. McKennis has submitted such a proposal which is attached. It suggests a twelve month budget of $67,870 which is very close to the monthly rate at which he actually spent the $45,0D0 appropriated for this ynar. (This budget is subject to scrutiny.) 8IGN7FICANCE There has been a f eeling among the staff and several Board memb'ers, I be]3eve, that highlyspecific and sensitive immuno assays for nicotine and its metabolites, requiring only smal:l quantities of blood serue and speedy as well as simple in application, could open a new era in "biochemical pharmacology" of nicotine. Labe]led antibodies applicable to locating binding sites in tissues could greatly augment the patentiaLs of such agents. A long list of "practical° questi'ons that might be solved by use of such agentb has accumulated. If we now have a first-class team avsilable for cooperation on the two phases of the research, a coatinuatic+n of support for both phases seems justified. R.C.H. RCH/lp Enals. P.S. The "official" signed copsr of the application wii]l be forthcoming c=entarily. Dr. McKennis is also supplying cotinine A-axide and nicotine R-'oacEde for other projects.