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Minerva Urologica e Nefrologica 2003 March;55(1):57-66


language: English

New monoclonal antibodies in renal trans-plantation

Vincenti F.

Kidney Transplant Service University of California, San Francisco, CA, USA


A ­decade of spec­tac­u­lar in­no­va­tion in main­te­nance im­mu­no­sup­pres­sion ­drugs has re­sult­ed in dra­mat­ic re­duc­tions in ­acute re­jec­tion and im­prove­ment in ­short and ­long ­term out­come af­ter re­nal trans­plan­ta­tion. However the new ­drugs con­tin­ue to ­lack spec­i­fic­ity, ­many re­quire fre­quent ther­a­peu­tic ­drug mon­i­tor­ing and all are as­so­ciat­ed ­with ­acute and chron­ic tox­ic­ities. The new bi­o­log­ic ­agents, mono­clo­nal anti­bod­ies (chi­mer­ic, hu­man­ized, and ful­ly hu­man) and re­cep­tor-fu­sion pro­teins, ­lack im­mu­nog­e­nic­ity, ­have ­long ­half-­life and pro­longed bi­o­log­ic ef­fects, re­quire inter­mit­tent ad­min­is­tra­tion and ­have min­i­mal tox­ic­ity. The spec­i­fic­ity and se­lec­tive­ly of the tar­gets of the new bi­o­log­ic ­agents ren­der ­them ­less tox­ic ­than the ­oral main­te­nance ­drugs and ­thus ­could pos­sibly re­place the main­te­nance ­drugs ­most as­so­ciat­ed ­with ­long-­term tox­ic­ity ­such as the cor­ti­cos­ter­oids and the cal­ci­neu­rin in­hib­i­tors. The re­cent­ly in­tro­duced ­anti-inter­leu­kin 2 re­cep­tor (IL-2R) mono­clo­nal anti­bod­ies (mAbs) are the pro­to­type of fu­ture bi­o­log­ic ­agents; se­lec­tive, ­safe, and in­duc­ing pro­longed bi­o­log­ic ef­fects. The IL-2R mAbs ­have ­been ­used ­with a va­rie­ty of main­te­nance im­mu­no­sup­pres­sion reg­i­mens dou­ble ther­a­py ­with cy­clo­spo­rine and pred­ni­sone, ­triple ther­a­py ­with cy­clo­spo­rine, az­a­thi­o­prine and pred­ni­sone and ­with new­er reg­i­mens ­such as cy­clo­spo­rine or ta­crol­i­mus, my­co­phen­o­late mofe­til (MMF) and pred­ni­sone, and ­most re­cent­ly ­with si­rol­i­mus, MMF and pred­ni­sone. The ma­jor ­thrust of the new bi­o­log­ics in clin­i­cal de­vel­op­ment is to ­block the co-stim­u­la­to­ry path­way. The ­first at­tempt at block­ade of the CD40-CD154 ­with ­anti-CD154 mAbs was dis­ap­point­ing. Anti-CD 154 ther­a­py was as­so­ciat­ed ­with throm­boem­bol­ic ­events and ­acute re­jec­tion. Attempts at block­ing the CD28-B7s (CD80-CD86) path­way are cur­rent­ly under­way ­with the re­cep­tor fu­sion pro­tein, LEA29Y a sec­ond gen­er­a­tion CTL4Aig, and hu­man­ized mAbs to CD 80 and CD86. LFA1, an ad­he­sion mole­cule ­that al­so par­tic­i­pates in the co-stim­u­la­to­ry path­way, has al­so ­been tar­get­ed ­with a mAb ­that ­binds to the CD11a ­chain of LFA1. Efalizumab, a hu­man­ized ­anti-CD11a mAb, was ­shown in a ­phase I ­trial to be po­ten­tial­ly ef­fec­tive in re­nal trans­plan­ta­tion. A hu­man­ized ­anti-CD45 RB mAb is cur­rent­ly in pre-clin­i­cal stud­ies and ­will like­ly be test­ed in a ­phase I ­trial of re­nal trans­plan­ta­tion with­in 1 ­year. While ex­cel­lent re­sults ­with ­anti-CD45 RB mAbs ­have ­been pub­lished in ex­peri­men­tal trans­plan­ta­tion, the mech­a­nism of ac­tion of ­anti-CD45 RB mAbs re­mains to be de­ter­mined. Several anti­bod­ies ­that are cur­rent­ly ap­proved for non-trans­plant in­di­ca­tions are cur­rent­ly ­used in sin­gle cen­ter clin­i­cal ­trials in re­nal trans­plan­ta­tion in­clud­ing Campath 1 H, a hu­man­ized ­anti-CD52 mAb, Rituxamab, an ­anti-CD20 chi­mer­ic mAb, and Infliximab an ­anti-TNFα chi­mer­ic mAb. In ad­di­tion, sev­er­al hu­man­ized mu­tag­e­nized ­anti-CD3 mAbs, huOKT3γ1, agly­co­syl CD3 and HuM291 ­have ­been ­used in lim­it­ed ­trials in re­nal trans­plan­ta­tion but ­have yet to ­have a for­mal clin­i­cal de­vel­op­ment. Humanized mAbs and re­cep­tor fu­sion pro­teins of­fer the po­ten­tial of pro­vid­ing re­nal trans­plant re­cip­ients ­with a nov­el al­go­rithm for im­mu­no­sup­pres­sion ­that ­relies on chron­ic inter­mit­tent intra­ve­nous ad­min­is­tra­tion of ­safe, non-tox­ic ­agents re­plac­ing ­oral ­drug ther­a­py main­te­nance.

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