Human lymphotoxin mutein lacks hypotensive activity but has higher in vivo antitumor activity than lymphotoxin or tumor necrosis factor

ABSTRACT Aseriousdrawbackoftumornecrosisfactor a (TNF)asaclinicalantitumoragentisthatitalsohashypotensiveactivity.Toovercomethisproblem,derivativesofitssistercytokinelymphotoxin(TNF- b orLT)wereprepared.Oneofthem,mutein2(Mut2)hasadeletionofaminoacids1–7butcontainssubstitutedaminoacids,Met-Phe-Proatpositions8–10ofthematurehumanLT.Thismuteinhasnohypotensiveactivityatthemaximumdose(10mg y kg)testedonrats.Incontrast,amuchlowerdose(1mg y kg)ofTNFandLTcausedasignificantbloodpressuredrop. Invivo studiesrevealedthatMut2wasmoreeffectivethanTNForLTagainstMethA(amousetumorline)asjudgedbythetherapeuticratio[calculatedasLD 50 (dosethatkills50%oftheanimals) y ED 50 (dosethatreducesthetumorsizeby50%)].Withfiveotherdifferentmousetumorsandtwodifferenthumantumors,Mut2wasalsoeffectiveandtheeffectivenesswascomparableorsuperiortothatofTNForLT.TheseresultssuggestthepossibilitythatthisderivativemaybeusableasaclinicalantitumoragentwithouttheserioussideeffectsassociatedwithTNF. Variousattemptshavebeenmadetocreatemuteinsoftumornecrosisfactor(TNF)andlymphotoxin(LT)toimprovetheirtherapeuticvalues(1).ResultsoftheseexperimentssuggestthatuptonineNH