NATURE BIOTECHNOLOGY VOL 17 JULY 1999 http://biotech.nature.com 621

CORRESPONDENCE

Plant ferritin and human irondeficiencyTo the editor:The paper by Goto et al.1 in your Marchissue highlights overexpression of the ironstorage protein ferritin in transgenic plantsas an approach for treating iron deficiencyin humans. Goto et al. overexpress iron inseeds, achieving a threefold increase in ironcontent in seeds, levels comparable toexperiments in my laboratory in which fer-ritin was overexpressed in leaves2. Anothergroup has shown that oral administration ofplant ferritin can alleviate iron deficiencyanemia in rats3. These findings have pro-mulgated the idea that iron-fortified trans-genic plants overexpressing ferritin could beused to mitigate iron deficiency in thehuman diet1.

Iron uptake, however, is not determinedonly by levels of iron storage proteins.Complex interactions between plant andsoil within the rhizosphere also profoundlyinfluence iron content. Solid phases con-trolling iron solubility in soils, chemicalspeciation of iron in solution, importanceof redox in the solubilization of iron, andthe role of synthetic and natural chelates intransport processes that occur near rootsare among soil-dependent factors deter-mining iron bioavailability4. In addition,plant iron uptake mechanisms are inti-mately associated with loading processes ofother metals, some of them being poten-tially toxic for humans. Ferritin overaccu-mulation in transgenic tobacco leaves leadsto excessive iron sequestration and theactivation of iron transport systems, asrevealed by an increase in root ferric reduc-tase activity2. Independently, it has beenreported that iron-deficiency activation ofthe IRT1 ferrous iron transporter was mostlikely responsible for cadmium loading ofpea plants5. In grasses, iron(III) uptakeoccurs through phytosiderophores of themugineic acid family; this transport sys-tem, activated under the above conditions,is also capable of transporting metals suchas zinc and probably copper6.

In the light of these findings, the behav-ior of transgenic plants overexpressing fer-ritin with regard to iron and heavy-metalloading under various soil conditionsshould be addressed in future experiments.

Only after the risks of toxic metal loadinghave been deemed acceptable can suchplants be introduced into the human foodchain.

Jean-François BriatBiochimie et Physiologie Moléculaire

des Plantes ENSA-MCNRS/INRA

F-34060 Montpellier cedex 1, Francebriat@ensam.inra.fr

1. Goto, F. et al. Nat. Biotechnol. 17, 282–286 (1999).2. Van Wuytswinkel, O. et al. Plant J. 17, 9397 (1999).3. Beard, J.L., Burton, J.W. & Theil, E.C. J. Nutr. 126,

154–160 (1996).4. Lindsay, W.L. In Iron in plants and soils (ed.

Abadia, J.) 714 (Kluwer, Amsterdam; 1995).5. Cohen, C.K. et al. Plant Physiol. 116, 1063–1072

(1998).6. von Wiren, N., Marschner, H. & Romheld, V. Plant

Physiol. 111, 1119–1125 (1996).

Human monoclonal antibodies: Theemperor’s new clothes?To the editor:With the advent of human immunoglobu-lin transgenic animals, where megabase-sized human DNA has been introducedinto the mouse germline, the traditionalapproach to producing monoclonal anti-bodies has come into vogue again. The rea-son is that well-established technologies,developed since the introduction of B cellhybridomas in 1975, can be utilized to gen-erate human monoclonal antibodies.Human monoclonal antibodies have forthe last 20 years been the goal of every sci-entist interested in immunotherapy ofhumans, since these molecules evoke aminimal immune response, a severe prob-lem associated with the use of mouse mon-oclonal antibodies in the clinic. However,since the first mouse monoclonal antibod-ies were introduced, a completely newapproach was published in the beginningof the 1990s, namely phage display ofhuman antibodies, where the diversity ofthe entire humoral immune response couldbe created in a small test tube. Overnightthe monoclonal antibody technology wasdeclared obsolete, since phage display ofantibodies was put forward as a muchfaster and more robust alternative. Whenthe arguments are put forward in favor oftoday’s new kid on the block—the trans-genic mouse—history repeats itself but in areverse manner, i.e., now monoclonal anti-bodies are the fast track to the clinic1. Thisanalysis is being pushed on the scientificcommunity by analysts to investors of thebiotech industry, probably not aroundwhen the phage antibodies were raised tothe skies2. What also appears to be forgot-ten is that no matter how human theimmune response of the transgenic mouseis, the problem of selecting a fusion partnerto immortalize the B cell repertoire still

remains the same. When “totally” humanmonoclonal antibodies are produced fromhuman immunoglobulin, transgenic micemyelomas of mouse origin are used asfusion partners3,4. The main problem isthen the glycosylation pattern the humanantibody ends up with, which is far fromhuman and contains the Gala1-3Galresidue. It is well known that human indi-viduals contain a human anti-Galal-3GalIgG antibody titer of up to 100 mg/ml (ref.5), which immediately will complex an invivo administered human antibody derivedfrom a transgenic mouse. This concern waspublished by us in 1993, based on theobservation that the serum half-life ofmouse monoclonal antibodies was inverse-ly proportional to the antibody content ofGalal-3Gal residues6. It was quite clear thatif an antibody contained Galal-3Galresidues it would not survive for long in thehuman circulation. On the other hand,human monoclonal antibodies derivedfrom EBV cell lines showed no evidence ofthe Galal-3Gal residue and did conse-quently not react with the human anti-Galal-3Gal IgG antibodies. Does then thetransgenic animal approach offer anyadvantages over e.g. phage displayed anti-bodies? The major advantage is not the oneput forward by biotech investors but israther the access to the affinity maturationmachinery of the mouse resulting in trulyhigh affinities—albeit a feature also foundin highly functional antibody libraries. Insummary, the scientific achievement inconstructing the human immunoglobulintransgenic mice is on the highest level butthe commercial arguments, fueled by thebiotech investors, are controversial and illfounded, where one major limiting factoris simply forgotten.

Carl A.K. Borrebaeck Department of Immunotechnology

Lund UniversityLund, Sweden

carl.borrebaeck@immun.lth.se

1. Sherman-Gold, R. Gen. Eng. News 17, 4 (1997). 2. Kim, J.H., & van den Broek, R.A. Equity research.

The renaissance of antibodies, Biotechnology Res.Report, Hambrecht & Quist LLC.

3. Mendez, M.J. et al. Nature Genetics 15, 146–156.(1997)

4. Fishwild, D.M., et al. Nature Biotechnology 14,845-851 (1996).

5 . Gallili, U. Immunol. Today 14, 480–482.6. Borrebaeck, C.A.K., Malmborg, A., Ohlin, M.

Immunol. Today 14, 477–479 (1993)

ErratumIn the June issue, the Research Analysisarticle "Nuturing nature: engineering newantibodies" (p. 538) was printed with anincomplete figure. The correct figure isavailable with the online version of thearticle.

Letters may be edited for space and clarity.They should be addressed to:CorrespondenceNature Biotechnology345 Park Avenue SouthNew York, NY 10010-1707, USAor sent by e-mail to biotech@natureny.comPlease include your telephone and fax numbers.

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