267
biotopics slightly displxc~l. I: is not clear why this leads to the obscrvcd lower OXTgen affinity of Fib Presbyrcrian. The basis for a blood substitute structure changes The minimal (the introduction of Gly, B,,,, Asn -* Ly:;, and Val --t Met at the amino tcnnini of the di-a- and P-chaiqs) of the mutanI rHbl.l as compared with normal haetnoglobin. may mean that a~ immune response (which might lead to hypcsensicivity or cvcn autoimmune problems) in the human pacienr, is unlikely. The ox--gen-binding propsrtics ot rHbl.1 arc cornparablc with those of whole blood. 11, the rat, the half-life of the
rHbl I n~olccule was two to :hrcc times grcatcr than a control Imemoglobin in which tbc ru-chains were not fused through Gly. Althorlgh &is hali4& was still only two hours, extrapolating from the normal pattern of pharmaci .kinctics ofinjectcd lab&d prowins &twccn mice and humans, it lwy be considerably longer in man. The authors of ihc paprr conclude chat they have the basis for a blood substiturc and Somatogcn recently indicated they were proceeding with I’basc I trials of rNbt .l. References
Antibody engineering - how to make useful therapeutics KBhlcr and Milstcin first described hybridoma ttichnoloh~~ 17 ycnrs ago, and 12 ycm hnvc passed since a nrtrnorlc~n~l Antibody jw>Ab) was first used for therapy in a human being. In spite of tbc fact thr;t a number of murinc, and sonic human, mAbs have undergone clinical trials for the diagnosis and therapy of cancer and other sclccted diseaws, M. Scharfi (A. Einstein Collcgc, New York, NY, USA), point& nut in his introduction to a recent intcmational confcrcnce*: that it is surprising thnr only one mAb has been approved by the FDA for therapy in the USA, and that only one other is dcstincd for approval in the near timire. The main topics prescntrd at the conference focused on tcchnologicai issues which have contributed to this delay. These involve, primarily, optimizing approaches to gcncrating antibodies wirh desired charactcriscics, and include the trchnolob~ involved in immortalizing B cells that produce useful andbodies, gcncrating antibodies or antibody
tirgmcncs which, sin~:dtaneounly (1) bind well. (3) arc poorly immunogenic, and (3) displq fcdturrs of pharniaccutical rclwmcc for human thcraFcutic uw. The affinity fence: Nature’s way E Ghcrardi (ICRF, Cambridge. UK) discussed the stratqy cmploycd by the immune sywm in animals to gcneratc high-atfinity antibodies. This involves the gcncration of primary (usually low-a%nity) antibodies by .xlcction from the available pool of heavy (H)- and light (L)chain combinations. This is followed by the gcncratinn of a large number of somatic mutants of the 0rigin.J H-L pair among which high-a%nity variants arc sclcctcd. Thus, the animal’s wategy for producing highaffinity antibodies involves extc-nrive wginecring of the antigen-binding site through repeated rounds of mutation and selection. It is possible that this seratcg could be inGrated. to 317rstcnt. to generate mature antibodies irr &o, and current work in several laboratories is csploring the powntial of this approach (WC M. J. Gcisow, TIBTECH l(!, 75-76. 1993; and D. J. Chirwell and J. McCa&ty, TIB7’ECH 10. W-84.
1992). 0 1992. Eisevier Science PubIshers Ltd (UK1
The transgenic way M. Briiggcmann (,4FRC, Cambridge, UK) approached the problem of constructing rcpcnoires of buman at ltibodics using tranigwic mice ahcr imertion of cithcr ~;cmhnc or pcrmrranqd inmun~globin gcnc\. rcnrrangcd H- or Ll’rodustivcly chain genes can bc altcrcd ilt the ~nousc B cells by somatic mutation ri,l!owing antigen selection. Ucing diffcrcnt approaches, rcarrangcd Lchain gznrs wcrc inserted into the ~IOLISC germlinc. lnr of hybrid proteins, with each protein presenting an oligopcptide of unique amino acid sequence on its surface. These peptide libraries can then bc screened for &malts that possess a desired property, such as the ability to bind a specific antibody or receptor. When proteins such as phage capsid proteins are used as s&olds to present oligopcptide antigens, the coding scqueucc for the pcptidc insert may be incorporated into the capsid pro.. tcin gene. ‘The resulting hybrid capsid protein is sccrctcd into the medium, thus ti~cilitating large-scale tAb. Tbe combination of the amino acid sequcnccs of the s&ted pcptidcs defines a consensus that is rclatcd to the antigen that was used to raise the rnA’b used in screen _ ing the pcptides. Thssc findings suggest that phage-prcsrnt”tioii tcchnoloby can bc used to map the imrnunogcnic rpitopes of a given protciu ofunknown structure and to select peptidcs that mimic the couformation of 3 natural cpitopc. IBTECHAUGUST 1992 (VOL101
Engineering mouse rnAbs for cancer immunotherapy _. and radiotherapy R. Or!;ndi iIstituto Nazionalc Tumori, Milano; Italy) cloned variable domains of murine mAbs to obtain molecules suitable for iri iJi1jo cancer immunotherapy of breast, ovarian and lung carcinomas. The specific anti-human mammary carcinoma mAb MBrI was expressed as a simple chimeric mAb, retaining the characteristic of specific binding to tumor cells and tissues conferred by the murine domains. The hl;man constant (C) region conferred additional ADCC (antibodydepcndcnc cellular cytotoxicity) features in the prcsencc of human lymphocytes acrivatcd by IL-2. The only drawback observed was a fivefold decrease in the binding ability of the chimeric mAb. (See also M. W. Fsnger and 1’. M. TIBTECH 0, 375-380, Guyrc, I991 .) The cw-subunit of the IL-2 rcceptor (IL-2Rcl) was selected by T. A. Waldmann (NIH, Bethesda, MD, USA) as a target for immunoradiotherapy due to its expression by abnormal and activated T ccIIs in ccrtain ncoplasias of mononuclear cells, selected autoimmunc disorders, and organ transplant rqjection. Normal r&ting cells do not express the inducible IL-2Ra. The urotnisinz results obtained with mAb against the unmodified anti-IL-3Ra used in adult T-cell lrukemia (ATL) led to the preparation of humanized antiIL-2Ra (CDR Icornplcmentarity determining region] from the ~OLISC mAb linked to rl framework derived from human lgG,#). The resulting chimcric structure (comparcLi with the untnodified anti-IL-2Ra) displayed reduced immunogcnicity and improved pharmacokinetics, along with ADCC with human mononuclear cells. A clinical trial using the anti-II,-2Ra anncd with toxins or with aand P-emitting radionuclidcs has shown no toxicity in the majority (i.e. five out of sis) of uatients with ATL. The onlvi side effects wcrc a modest granulecytopenia and thrombocytopcnia &crvcd in one patient. The partial or scptaincd compicto remission after ““Y-IL-21~~~ therapy indicated that IL-2P.a :lirrctcd therapy represents a new approach to the trcatmcnt of certain neoplastic diseases, autoimmune disorders, and for the prevention of transplant rejection.
Xecombinamt toxin conjugates as novel therapeutic agents (NIH, Bethesda, D. ?itzGerald MD, ‘USA) presented an overview on the recent advances in the prcpantic,> of chimeric immunotoxins. Cell-killing and antitumor activities have been demonstrated when chirneric toxins have been targeted to tumor cells bearing high levels of the epidcrmal growth factor receptor (EGF-R), the IL-2 receptor (IL-7R) or the ii-6 receptor (IL-6R). Likcwise, immunotoxins made thorn native B3 (or Fv fragments of this antibody) displayed significant antitumor activities against antigcnpositive tumor cells. In vitro and r’n t&r, modulation of cytotoxic cells with multispecific antibodies Evidence from a number of laboratories suggests that out of ehc most interest&g and potentially useful saolications of bisoccific anti. *, bodies (bsAb) is in the modularion of T, NK and monocyte activities. M. _I. Glennie (Tenovus Research Laboratories, Southampton, UK) presented the results obt&ed with i bissecific antibodv which cross-links thi TCR/CD3 &mples to CD’. The intravenous or intrapcritoneal injection into rats of 5-50 1J-g of bsAb (anti-TCR x anti-CD2) caused a decrease in circulating lymphocytes and no sigms of toxic shock. Another significant result of this csperimcnt was the activation of CD4+ and CDs+ splenocytes and increased esprcssion ofMHC (major histocompatibility complex) class I1 antigen, probably as a result of IL-4 production. In addition, these cells showed remarkable proliferation in IL-2 and significant increases in natural-killer (NK) and T-cell cytotoxic activity against tumor rarg&s. F. Malavasi (Univ. Torino. Italvl reported the results of a coUaborativc effort (P. Nisricti, R. Mortariui, L. B. DeMonte, A. Mazzocchi, M. Madani, F. Malavasi, G. l’arlniani, P. G. Nataii and A. Anizhini J. Clirl. Iflm:cr., in press). Gene transfer by rctrovirus-derived shuttle vcctos has been uqcd to generate a wide panel of bsmAbs (bispccific monoclonal antibodies). nrgcting molecules expressed on cytotosic cells (i.e. T-lymphocytes and NK cells) against a human melanoma-associated antigen (HMW-MAA), carcinoembryonic antigen (CEA): and common acute lymphoblaqtic Icukcmia antigen (CALLA). Other bsmAbs
269
f OYUWl (e.g. a-CD3 x a-CD2) specific for lymphocyte receptor molecules simultaneously expressed by the et&tars have been produced. Applications have been tested in irr vitro models, maizdy in order to overcome the variation in susceptibility to cyeotoxic T-lymphocyte (CTL)-mediatcd lysis within individual tunlours. The cunclusicus are that the concurrent USCofdifferent bsmAbs to trigger may discrete activation pathways improve the general performance and may find practical application in cancer immu-lotherapy. Other apphcatlofic concern their use for intracellular routing and targeting of bsmAbs carrying toxins, while their USC to destroy ccl1 populations cxpressingtargct molcculcs (c.g. cells infected with HIV) appears highly promising. 1). M. Segal (NCI/NlH, Bethesda, MD, USA) rcvicwed the mechanisms involved in targeted cytolysis, emphasizing the secretion of factorsthat can biock the grow& of both tumor target cells and bystander tumor cells. The treatment of mice bearing intraperitor,eal human ovarian carcinoma with human T cells targeted with bsmAbs led to a rapid removal of most tumor cells from the peritoneum, and increased the survival of the mice. The efficacy of targeted T cells for treating humau cancer is currently being tested in clinical trials - preliminary results arc Promising. Melanoma immunotherapy with antiidiotypic mAb S. Ferrone (Vaihalla, NY, USA) reported the etfects irr t&o of the treatment of patients with a atrtiidiotypic mAb, whic!l bears the internal
image of HMW-MAA. The treatment induced an increase in the levels of anti-mouse antibodies iu nearIy all the patients w:th melanoma, but elicited anti-HMWMAA immunity in only about 6O’h of the immunized patients. The human HMW-MAA binding antibodies elicited upon mAb treatment arc Lath IgM and I&. Their titrcs arc markedly enhanced by the conjugation ofthe mAb with a carrier and the administration with an adjuvant, while the titres are not affected by the delivery of cytoxan. The conclusiou is that the induction of anti-HMWMAA immunity by immunizatiot~ with antiidiotypic m.\b is associated with a stati:;:ically significant survival prolongation in patients with melano1na.
may bc overcome a:ltibodics designed effector functions
by engineered with improved (i.c. incrcascd cotllpleIllcllt Fc-dcpcndcnr and c)-totoxicity) and to reducing to almost nil the imnlunogcnicity ofthc therapeutic antibody. (see also C. Cunningham and W. J. Harris, TIBT’ECH 10, 112-l 13, 1992.)
was more besides.. . also included besides awful weather - an updating on CD3 [by C. Tcrhorst (Harvard Medical School, Boston, MA, USA)], and on gene therapy mod& [R/1. D!arsc (NIH, Bcthcsda, MD, USA)/, satcllitc mectin~ (‘Molecular analysis of primary i~~~~~nunodcticio~cics’, ‘Cell and tissue engineering iI1 biomedicine’) and a round table on ‘Uiotcchnology in the EEC’. This the immune has been the seat of discussion of Reprogramming system with mAbs problems that are still burdcniug sciIt is known that immunosupence and rcscarch (elthcr in acadcnlic pressive drugs pcl?a!ize the wl~olc or in industrial organizations) in immune s-ystcIn for the misEurope. demeanors of only a sn~all proAnd finally, 1 note of optimism: portion of the lymphocytes. In the the data prcscntcd by the European attempt to overcome this problem, groups was original and of high quality, rctlccl;ing a slew wave of H. Waldmann (Cambridge, UK) basic science from Europe. Let us devised ways of inducing tolcrancc vow that this posit& trend may find to selected antigens (tolrrization). This was achieved iu mice by using further and turgctcd support by the Uiotcch proh?am that is to bc short couucs of mAb to CD4 and CD& which conferred tolerance to launched by dlc EEC soon. forcigu proteins, heart, skin alld bone marrow grafts. The tolerant state achieved at the price of a dcstructioo of a limited number of lymphocytes - was profound and rcsism?lt to the infusion of normal lyniphocytcs. This resistance was itselfmcdiatcd by host T cells that actively maintained the tolerizrd state. The iirnitatiour to this model to hunlans transferring There
The conferz:lce
Biopatmts: a sense of order
Since the discovery of fire, it scc~lls, mankind has worried about the implications of ‘inventiveness’. What can the inventor do with the discovery? Even worse, what could someone else do with it?! Should discoveries bc put to use for the benefit of all, or for the profit of a ft-w? Who should decide what is to bc done - and how can the decisions be enforced? C’1992, Elsebier Science Publishers CM [UK)
Mul~lan invcntivencss has rewltcd in a constant tlow oi new products, atli of new applicaGcnr f&r evicting products. With the uvolutiou of the various disciplines of science and technology, so too arose the nrrd hr some sort of regulation with reg‘trd to recognition and/or profit t)om an individual’s own work, The patcnting system has devclopcd ro fill that need. Tccl~~~olo~~, generally,
ic ‘patentable if utile’ (Ii. 13izlcy. Hepworth, Laurence ,~nd fiizlcy, IHarlow. UK). Uiotcclmolo~~ is not quite so simple Where patents arc concerned, life and life-derived products pre+z!lt a special challcngr, and may bc subjcrt to certain exclusion clauses. tlowever, since 1980 it cau no longer bc said that something is not pnrent;tble just because it i?: Iwing. Patent protcctiou t6r a limited rang’- of living matter has already been granted, a13d biotechnolo~~~ 11.1~ advanced so rapidly in recwt years tht tllcic is :BTECH AOGUST 1992WL
10)
biotopics slightly displxc~l. I: is not clear why this leads to the obscrvcd lower OXTgen affinity of Fib Presbyrcrian. The basis for a blood substitute structure changes The minimal (the introduction of Gly, B,,,, Asn -* Ly:;, and Val --t Met at the amino tcnnini of the di-a- and P-chaiqs) of the mutanI rHbl.l as compared with normal haetnoglobin. may mean that a~ immune response (which might lead to hypcsensicivity or cvcn autoimmune problems) in the human pacienr, is unlikely. The ox--gen-binding propsrtics ot rHbl.1 arc cornparablc with those of whole blood. 11, the rat, the half-life of the
rHbl I n~olccule was two to :hrcc times grcatcr than a control Imemoglobin in which tbc ru-chains were not fused through Gly. Althorlgh &is hali4& was still only two hours, extrapolating from the normal pattern of pharmaci .kinctics ofinjectcd lab&d prowins &twccn mice and humans, it lwy be considerably longer in man. The authors of ihc paprr conclude chat they have the basis for a blood substiturc and Somatogcn recently indicated they were proceeding with I’basc I trials of rNbt .l. References
Antibody engineering - how to make useful therapeutics KBhlcr and Milstcin first described hybridoma ttichnoloh~~ 17 ycnrs ago, and 12 ycm hnvc passed since a nrtrnorlc~n~l Antibody jw>Ab) was first used for therapy in a human being. In spite of tbc fact thr;t a number of murinc, and sonic human, mAbs have undergone clinical trials for the diagnosis and therapy of cancer and other sclccted diseaws, M. Scharfi (A. Einstein Collcgc, New York, NY, USA), point& nut in his introduction to a recent intcmational confcrcnce*: that it is surprising thnr only one mAb has been approved by the FDA for therapy in the USA, and that only one other is dcstincd for approval in the near timire. The main topics prescntrd at the conference focused on tcchnologicai issues which have contributed to this delay. These involve, primarily, optimizing approaches to gcncrating antibodies wirh desired charactcriscics, and include the trchnolob~ involved in immortalizing B cells that produce useful andbodies, gcncrating antibodies or antibody
tirgmcncs which, sin~:dtaneounly (1) bind well. (3) arc poorly immunogenic, and (3) displq fcdturrs of pharniaccutical rclwmcc for human thcraFcutic uw. The affinity fence: Nature’s way E Ghcrardi (ICRF, Cambridge. UK) discussed the stratqy cmploycd by the immune sywm in animals to gcneratc high-atfinity antibodies. This involves the gcncration of primary (usually low-a%nity) antibodies by .xlcction from the available pool of heavy (H)- and light (L)chain combinations. This is followed by the gcncratinn of a large number of somatic mutants of the 0rigin.J H-L pair among which high-a%nity variants arc sclcctcd. Thus, the animal’s wategy for producing highaffinity antibodies involves extc-nrive wginecring of the antigen-binding site through repeated rounds of mutation and selection. It is possible that this seratcg could be inGrated. to 317rstcnt. to generate mature antibodies irr &o, and current work in several laboratories is csploring the powntial of this approach (WC M. J. Gcisow, TIBTECH l(!, 75-76. 1993; and D. J. Chirwell and J. McCa&ty, TIB7’ECH 10. W-84.
1992). 0 1992. Eisevier Science PubIshers Ltd (UK1
The transgenic way M. Briiggcmann (,4FRC, Cambridge, UK) approached the problem of constructing rcpcnoires of buman at ltibodics using tranigwic mice ahcr imertion of cithcr ~;cmhnc or pcrmrranqd inmun~globin gcnc\. rcnrrangcd H- or Ll’rodustivcly chain genes can bc altcrcd ilt the ~nousc B cells by somatic mutation ri,l!owing antigen selection. Ucing diffcrcnt approaches, rcarrangcd Lchain gznrs wcrc inserted into the ~IOLISC germlinc. lnr of hybrid proteins, with each protein presenting an oligopcptide of unique amino acid sequence on its surface. These peptide libraries can then bc screened for &malts that possess a desired property, such as the ability to bind a specific antibody or receptor. When proteins such as phage capsid proteins are used as s&olds to present oligopcptide antigens, the coding scqueucc for the pcptidc insert may be incorporated into the capsid pro.. tcin gene. ‘The resulting hybrid capsid protein is sccrctcd into the medium, thus ti~cilitating large-scale tAb. Tbe combination of the amino acid sequcnccs of the s&ted pcptidcs defines a consensus that is rclatcd to the antigen that was used to raise the rnA’b used in screen _ ing the pcptides. Thssc findings suggest that phage-prcsrnt”tioii tcchnoloby can bc used to map the imrnunogcnic rpitopes of a given protciu ofunknown structure and to select peptidcs that mimic the couformation of 3 natural cpitopc. IBTECHAUGUST 1992 (VOL101
Engineering mouse rnAbs for cancer immunotherapy _. and radiotherapy R. Or!;ndi iIstituto Nazionalc Tumori, Milano; Italy) cloned variable domains of murine mAbs to obtain molecules suitable for iri iJi1jo cancer immunotherapy of breast, ovarian and lung carcinomas. The specific anti-human mammary carcinoma mAb MBrI was expressed as a simple chimeric mAb, retaining the characteristic of specific binding to tumor cells and tissues conferred by the murine domains. The hl;man constant (C) region conferred additional ADCC (antibodydepcndcnc cellular cytotoxicity) features in the prcsencc of human lymphocytes acrivatcd by IL-2. The only drawback observed was a fivefold decrease in the binding ability of the chimeric mAb. (See also M. W. Fsnger and 1’. M. TIBTECH 0, 375-380, Guyrc, I991 .) The cw-subunit of the IL-2 rcceptor (IL-2Rcl) was selected by T. A. Waldmann (NIH, Bethesda, MD, USA) as a target for immunoradiotherapy due to its expression by abnormal and activated T ccIIs in ccrtain ncoplasias of mononuclear cells, selected autoimmunc disorders, and organ transplant rqjection. Normal r&ting cells do not express the inducible IL-2Ra. The urotnisinz results obtained with mAb against the unmodified anti-IL-3Ra used in adult T-cell lrukemia (ATL) led to the preparation of humanized antiIL-2Ra (CDR Icornplcmentarity determining region] from the ~OLISC mAb linked to rl framework derived from human lgG,#). The resulting chimcric structure (comparcLi with the untnodified anti-IL-2Ra) displayed reduced immunogcnicity and improved pharmacokinetics, along with ADCC with human mononuclear cells. A clinical trial using the anti-II,-2Ra anncd with toxins or with aand P-emitting radionuclidcs has shown no toxicity in the majority (i.e. five out of sis) of uatients with ATL. The onlvi side effects wcrc a modest granulecytopenia and thrombocytopcnia &crvcd in one patient. The partial or scptaincd compicto remission after ““Y-IL-21~~~ therapy indicated that IL-2P.a :lirrctcd therapy represents a new approach to the trcatmcnt of certain neoplastic diseases, autoimmune disorders, and for the prevention of transplant rejection.
Xecombinamt toxin conjugates as novel therapeutic agents (NIH, Bethesda, D. ?itzGerald MD, ‘USA) presented an overview on the recent advances in the prcpantic,> of chimeric immunotoxins. Cell-killing and antitumor activities have been demonstrated when chirneric toxins have been targeted to tumor cells bearing high levels of the epidcrmal growth factor receptor (EGF-R), the IL-2 receptor (IL-7R) or the ii-6 receptor (IL-6R). Likcwise, immunotoxins made thorn native B3 (or Fv fragments of this antibody) displayed significant antitumor activities against antigcnpositive tumor cells. In vitro and r’n t&r, modulation of cytotoxic cells with multispecific antibodies Evidence from a number of laboratories suggests that out of ehc most interest&g and potentially useful saolications of bisoccific anti. *, bodies (bsAb) is in the modularion of T, NK and monocyte activities. M. _I. Glennie (Tenovus Research Laboratories, Southampton, UK) presented the results obt&ed with i bissecific antibodv which cross-links thi TCR/CD3 &mples to CD’. The intravenous or intrapcritoneal injection into rats of 5-50 1J-g of bsAb (anti-TCR x anti-CD2) caused a decrease in circulating lymphocytes and no sigms of toxic shock. Another significant result of this csperimcnt was the activation of CD4+ and CDs+ splenocytes and increased esprcssion ofMHC (major histocompatibility complex) class I1 antigen, probably as a result of IL-4 production. In addition, these cells showed remarkable proliferation in IL-2 and significant increases in natural-killer (NK) and T-cell cytotoxic activity against tumor rarg&s. F. Malavasi (Univ. Torino. Italvl reported the results of a coUaborativc effort (P. Nisricti, R. Mortariui, L. B. DeMonte, A. Mazzocchi, M. Madani, F. Malavasi, G. l’arlniani, P. G. Nataii and A. Anizhini J. Clirl. Iflm:cr., in press). Gene transfer by rctrovirus-derived shuttle vcctos has been uqcd to generate a wide panel of bsmAbs (bispccific monoclonal antibodies). nrgcting molecules expressed on cytotosic cells (i.e. T-lymphocytes and NK cells) against a human melanoma-associated antigen (HMW-MAA), carcinoembryonic antigen (CEA): and common acute lymphoblaqtic Icukcmia antigen (CALLA). Other bsmAbs
269
f OYUWl (e.g. a-CD3 x a-CD2) specific for lymphocyte receptor molecules simultaneously expressed by the et&tars have been produced. Applications have been tested in irr vitro models, maizdy in order to overcome the variation in susceptibility to cyeotoxic T-lymphocyte (CTL)-mediatcd lysis within individual tunlours. The cunclusicus are that the concurrent USCofdifferent bsmAbs to trigger may discrete activation pathways improve the general performance and may find practical application in cancer immu-lotherapy. Other apphcatlofic concern their use for intracellular routing and targeting of bsmAbs carrying toxins, while their USC to destroy ccl1 populations cxpressingtargct molcculcs (c.g. cells infected with HIV) appears highly promising. 1). M. Segal (NCI/NlH, Bethesda, MD, USA) rcvicwed the mechanisms involved in targeted cytolysis, emphasizing the secretion of factorsthat can biock the grow& of both tumor target cells and bystander tumor cells. The treatment of mice bearing intraperitor,eal human ovarian carcinoma with human T cells targeted with bsmAbs led to a rapid removal of most tumor cells from the peritoneum, and increased the survival of the mice. The efficacy of targeted T cells for treating humau cancer is currently being tested in clinical trials - preliminary results arc Promising. Melanoma immunotherapy with antiidiotypic mAb S. Ferrone (Vaihalla, NY, USA) reported the etfects irr t&o of the treatment of patients with a atrtiidiotypic mAb, whic!l bears the internal
image of HMW-MAA. The treatment induced an increase in the levels of anti-mouse antibodies iu nearIy all the patients w:th melanoma, but elicited anti-HMWMAA immunity in only about 6O’h of the immunized patients. The human HMW-MAA binding antibodies elicited upon mAb treatment arc Lath IgM and I&. Their titrcs arc markedly enhanced by the conjugation ofthe mAb with a carrier and the administration with an adjuvant, while the titres are not affected by the delivery of cytoxan. The conclusiou is that the induction of anti-HMWMAA immunity by immunizatiot~ with antiidiotypic m.\b is associated with a stati:;:ically significant survival prolongation in patients with melano1na.
may bc overcome a:ltibodics designed effector functions
by engineered with improved (i.c. incrcascd cotllpleIllcllt Fc-dcpcndcnr and c)-totoxicity) and to reducing to almost nil the imnlunogcnicity ofthc therapeutic antibody. (see also C. Cunningham and W. J. Harris, TIBT’ECH 10, 112-l 13, 1992.)
was more besides.. . also included besides awful weather - an updating on CD3 [by C. Tcrhorst (Harvard Medical School, Boston, MA, USA)], and on gene therapy mod& [R/1. D!arsc (NIH, Bcthcsda, MD, USA)/, satcllitc mectin~ (‘Molecular analysis of primary i~~~~~nunodcticio~cics’, ‘Cell and tissue engineering iI1 biomedicine’) and a round table on ‘Uiotcchnology in the EEC’. This the immune has been the seat of discussion of Reprogramming system with mAbs problems that are still burdcniug sciIt is known that immunosupence and rcscarch (elthcr in acadcnlic pressive drugs pcl?a!ize the wl~olc or in industrial organizations) in immune s-ystcIn for the misEurope. demeanors of only a sn~all proAnd finally, 1 note of optimism: portion of the lymphocytes. In the the data prcscntcd by the European attempt to overcome this problem, groups was original and of high quality, rctlccl;ing a slew wave of H. Waldmann (Cambridge, UK) basic science from Europe. Let us devised ways of inducing tolcrancc vow that this posit& trend may find to selected antigens (tolrrization). This was achieved iu mice by using further and turgctcd support by the Uiotcch proh?am that is to bc short couucs of mAb to CD4 and CD& which conferred tolerance to launched by dlc EEC soon. forcigu proteins, heart, skin alld bone marrow grafts. The tolerant state achieved at the price of a dcstructioo of a limited number of lymphocytes - was profound and rcsism?lt to the infusion of normal lyniphocytcs. This resistance was itselfmcdiatcd by host T cells that actively maintained the tolerizrd state. The iirnitatiour to this model to hunlans transferring There
The conferz:lce
Biopatmts: a sense of order
Since the discovery of fire, it scc~lls, mankind has worried about the implications of ‘inventiveness’. What can the inventor do with the discovery? Even worse, what could someone else do with it?! Should discoveries bc put to use for the benefit of all, or for the profit of a ft-w? Who should decide what is to bc done - and how can the decisions be enforced? C’1992, Elsebier Science Publishers CM [UK)
Mul~lan invcntivencss has rewltcd in a constant tlow oi new products, atli of new applicaGcnr f&r evicting products. With the uvolutiou of the various disciplines of science and technology, so too arose the nrrd hr some sort of regulation with reg‘trd to recognition and/or profit t)om an individual’s own work, The patcnting system has devclopcd ro fill that need. Tccl~~~olo~~, generally,
ic ‘patentable if utile’ (Ii. 13izlcy. Hepworth, Laurence ,~nd fiizlcy, IHarlow. UK). Uiotcclmolo~~ is not quite so simple Where patents arc concerned, life and life-derived products pre+z!lt a special challcngr, and may bc subjcrt to certain exclusion clauses. tlowever, since 1980 it cau no longer bc said that something is not pnrent;tble just because it i?: Iwing. Patent protcctiou t6r a limited rang’- of living matter has already been granted, a13d biotechnolo~~~ 11.1~ advanced so rapidly in recwt years tht tllcic is :BTECH AOGUST 1992WL
10)
