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EDITORIAL REVIEW

Strategies in antibody therapy of cancer E. J. WAWRZYNCZAK & A. J. S. DAVIES Institute of Cancer Research, Sutton, England

(Acceptedfor publication 3 September 1990) In an alternative strategy, not dependent on the presence of the Fc portion, the anti-tumour antibody is used simply as a vehicle for the delivery to the tumour of an agent capable of stimulating a protective host response. Thus an antibody-cobra venom factor (CVF) conjugate was shown to inhibit the growth of a human melanoma cell line selectively in vitro and in vito; CVF activates the alternative pathway of complement by formation of a stable C3/C5-like convertase (Vogel & MullerEberhard, 1981; Vogel, Wilkie & Morgan, 1985). Agents that can attract macrophages to the site of tumour or activate those already present within the tumour, such as N-formyl-methionylleucylphenylalanine and muramyl dipeptide, have been attached to anti-tumour antibodies and shown to influence macrophage behaviour in vivo; however, no anti-tumour effects have been proven (Obrist & Sandberg, 1983; Obrist, 1987). A monoclonal antibody conjugate with interferon-a augmented the killing of a human osteogenic sarcoma cell line in vitro by peripheral blood natural killer (NK) cells and also led to the destruction of bystander cells (Flannery et al., 1985). A third strategy employs bispecific antibodies, generated either by chemical coupling or by hybridoma fusion, which possess two different antigen-binding specificities; one directed against the target antigen on the tumour cell and the other directed against a cell surface molecule of the effector cell. Such antibodies have been used to induce tumour cell lysis mediated through the action of cytotoxic T cells or K/NK cells (Clark, Gilliland & Waldmann, 1988; Songsivilai & Lachmann, 1990). Bispecific conjugates against the CD3/T cell receptor complex were demonstrated to trigger tumour cell lysis by class I MHCrestricted mouse and human T lymphocyte clones in vitro (Liu et al., 1985; Perez et al., 1985; Staerz, Kanagawa & Bevan, 1985). Anti-tumour effects were also observed in experimental animals when the bispecific conjugate and activated T cells were injected into the same body compartment as the tumour (Staerz & Bevan, 1986; Garrido et al., 1990). Similar triggering of T cellmediated lysis of tumour cells in vitro was demonstrated with a bispecific conjugate directed against the CD2 antigen (Goedegebuure et al., 1989). Human K/NK cells were also shown to be capable of lysing tumour cells pretreated with a bispecific conjugate recognizing the FcyRIII (CD 16) in vitro (Titus et al., 1987). The potential advantage of this approach is that the bispecific conjugate can bring about the selective lysis of the target cell by effector cells which have no inherent specificity for the target. A fourth strategy has been to direct the cytotoxic activity of class II MHC-restricted T helper cells by means of anti-tumour monoclonal antibody conjugates. The lysis of a murine B cell lymphoma cell line tagged with an antibody-keyhole limpet

INTRODUCTION The aim of drug targeting in the treatment of cancer is to focus therapeutic agents on tumour targets while sparing normal tissues from untoward damage. Two important aids in achieving this aim have been the differences that have been shown between malignant cells and their normal counterparts with regard to expression of cell surface antigens, and the development of monoclonal antibodies that can distinguish target from non-target cells. Tumour-associated antigens have been identified in all the common solid cancers, and the presence of various lymphocytedifferentiation antigens is diagnostic of many of the haematological malignancies. Antibody molecules have advantages in tumour targeting in that they can activate secondary immune effector mechanisms and can be used as carriers of cytotoxic agents and various biological response modulators. This review compares the different strategies of antibody therapy, both clinical and experimental, and points out their relative merits and limitations. Detailed expositions are to be found in several recent monographs (Vogel, 1987; Frankel, 1988; Rodwell, 1988; Sedlacek et al., 1988; Waldmann, 1988).

ACTIVATION OF ACCESSORY IMMUNOLOGICAL MECHANISMS Monoclonal antibodies can exert cytostatic effects if they bind to and interfere with the function of growth factor receptors; they are rarely cytotoxic without the help of accessory mechanisms. In these circumstances the simplest strategy for therapy using antibodies has been to use the inherent ability of these molecules to trigger complement-mediated cytotoxicity or antibody-dependent cellular cytotoxicity. The activation of such secondary effector systems depends on binding to the target cell and the presence of the Fc portion of antibody. Studies on experimental animals have established that inhibition of tumour growth in vivo is achievable in this way, although such treatments are considerably less effective in the case of wellestablished tumours or in widely disseminated disease. In clinical trials of intravenously administered monoclonal antibodies, the best results (including complete remissions) have been observed in patients with haematological malignancies; tumours in lymph nodes and solid tumours are generally refractory to treatment (Dillman, 1987). Correspondence: Dr E. J. Wawrzynczak, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton Surrey SM2 5NG, UK.

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haemocyanin (KLH) conjugate by a KLH-reactive mouse T helper cell line was demonstrated in vitro (Ochi et al., 1987). In this system, the target cell was competent to process the antigen and present it to the effector cell. Similarly, as reported in this issue, cytotoxic effects were demonstrated in vitro against a murine melanoma cell line by the combination of an antibodytuberculin (PPD) conjugate and a PPD-reactive mouse T helper cell line (Montgomery, Wing & Lachmann, 1990; Wing et al., 1990). In this case, the processing of the PPD antigen may not have been essential to permit recognition. Preliminary experiments suggested that the antibody-PPD conjugate could inhibit tumour growth in BCG-immune mice and might therefore be capable of inducing a delayed-type hypersensitivity response in the human BCG-immune population. The cytotoxic action of the effector cells was mediated by cytokine release consistent with the bystander cell cytotoxicity observed (Ochi et al., 1987; Wing et al., 1990). TARGETING OF CYTOTOXIC AGENTS A major limitation of antibody therapy mediated through the stimulation of accessory immunological mechanisms is the reliance upon the efficient recruitment of effector cells which may either not be present in sufficient numbers in solid tumours, or may have been compromised by disease or prior therapy, or are absent from immuno-privileged sites in the body. A potential solution to this problem is the use of monoclonal antibodies to target agents whose ability to exert cytotoxic effects is independent of the immune system of the host. The first strategy involves agents that have inherent cytotoxic activity but no intrinsic selectivity for the target cell unless directly coupled to antibody. Radionuclides emitting cell-damaging radiation, such as IIII or 90Y which decay to release fl-particles, have been linked to monoclonal antibodies by means of direct halogenation or via chemically coupled chelators and have been shown to cause regression of tumours in animals. In clinical trials of radioimmunotherapy, complete and partial remissions were obtained in a proportion of patients but haematological toxicity was a dose-limiting factor (Order et al., 1990). Thus, one potential advantage of f-emitting radionuclides, the ability to kill malignant cells at a distance of several cell diameters from the site of cell attachment, is balanced by the constant and undesirable irradiation of normal tissues by radioimmunoconjugate in the circulation. Several chemotherapeutic drugs with different mechanisms of action including alkylating agents (chlorambucil, melphalan), DNA intercalators (daunomycin, adriamycin), mitotic inhibitors (vinblastine, vindesine) and anti-metabolites (methotrexate, 5-fluorouracil) have been chemically conjugated to monoclonal antibodies, either directly or via macromolecular spacers such as human serum albumin (HSA),poly-L-glutamate or dextran (Rodwell, 1988). Antibody-drug conjugates only exert their cytotoxic effects following attachment to target cells, antigen-mediated internalization and lysosomal digestion to release free active drug within the cell. Inhibition of tumour growth in several animal model systems confirmed the selective action of drug immunoconjugates, but the few clinical trials reported have given little evidence of response. More potent antibody conjugates, immunotoxins, can be constructed by the covalent attachment of highly potent protein

toxins such as Pseudonmonas exotoxin A and diphtheria toxin, derived from bacteria, or ricin isolated from the castor bean Ricinus communis (Blakey et al., 1988; Frankel, 1988). The toxins kill cells by first attaching to them via specific receptors, gaining access to the cytosol and catalytically inactivating protein synthesis. To prevent binding to non-target cells, the binding sites of the toxins can be eliminated by chemical modification or by genetic manipulation of toxin genes. An alternative approach is to target either the non-binding enzymic portion of ricin, the A chain, alone or analogous ribosomeinactivating proteins such as gelonin and saporin. The advantage of immunotoxins of this type, in common with antibodydrug conjugates, is that their action is dependent upon target antigen binding and internalization. In addition, immunotoxins may be able to eliminate malignant cells that are resistant to chemotherapeutic drugs or radiation because they incapacitate cells by a quite distinct mechanism. Immunotoxins have been shown to inhibit the growth of a wide variety of murine and human lymphoid and solid cancers in vitro and in animals. In the limited clinical trials to date there has been evidence of positive responses but few complete remissions (Hertler & Frankel, 1989). The potential effectiveness of agents that act on the membrane at the cell surface and do not require internalization has been explored with tumour cell lines in vitro using antibody conjugates made with a phospholipase C (Flickinger & Trost, 1976) and a haemolytic toxin from the sea anemone Stoichactis helianthus (Avila, Mateo de Acosta & Lage, 1988). An alternative strategy uses the anti-tumour antibody to target an agent that has no toxic property in isolation but can be activated by external irradiation. The agents investigated include haematoporphyrin, which could be photoactivated to generate toxic oxygen radicals (Mew et al., 1983), and the nonradioactive isotope '0B, which liberates potently cytocidal x-particles on irradiation with thermal neutrons (Barth, Soloway & Fairchild, 1990). This strategy could potentially limit toxic side-effects by inducing cytotoxic activity only when the antibody conjugate has localized at the site of tumour. Both approaches are problematic because of the relatively high concentrations of each agent required to localize in the tumour, and the limited penetration of tissue by the activating radiation. The third strategy involves a two-stage system for targeting cytotoxic agents. In one version, a bispecific antibody conjugate recognizing both the tumour cell and the cytotoxic agent is allowed to localize at the site of tumour and is then used to capture the cytotoxic agent which is administered subsequently. The approach has been developed for the targeting of vinblastine, giving anti-tumour effects in animals (Smith et al., 1990); a methotrexate-HSA conjugate (Pimm et al., 1990); ricin and ricin A chain (Raso & Griffin, 1981; Webb et al., 1985; Robins et al., 1990); and saporin, giving selective anti-tumour effects in vivo (Glennie et al., 1988). This strategy is designed to avoid the difficulties of immunoconjugate synthesis and purification and may be useful to limit the non-specific toxicity associated with intact antibody conjugates, especially radioimmunoconjugates. So far the technique has not been applied to therapeutically useful radionuclides, although the localization of"'In has been demonstrated in tumour xenografts using bispecific antibody conjugates recognizing a bivalent indium-DTPA hapten (Goodwin et al., 1988; Le Doussal et al., 1990). Similar twostage targeting to tumour may be feasible by taking advantage

Antibody therapy of cancer of the strong non-covalent interaction between biotin and avidin or streptavidin (Hnatowich, Virzi & Rusckowski, 1987; Paganelli et al., 1988).

TARGETED ENZYME-MEDIATED CYTOTOXICITY that use either direct attachment of the strategies of A drawback cytotoxic or potentially cytotoxic agents to monoclonal antibodies or two-stage targeting to capture cytotoxic agents is that the effective dose of the agent which can be delivered to tumour is directly in proportion to the amount of antibody conjugate able to localize. This drawback can be overcome in principle by using the anti-tumour antibody to target an enzyme that has no direct effect on the tumour cell but which can catalyse the conversion of a non-toxic precursor to a toxic substance in situ. The first class of enzyme investigated are various oxidases that can generate toxic metabolites. A monoclonal antibodyxanthine oxidase conjugate, generating oxygen radicals in the presence of hypoxanthine, was selectively toxic to a human tumour cell line in tissue culture (Battelli et al., 1988). Likewise, a double immunoenzyme system comprising antibody conjugates with glucose oxidase and lactoperoxidase, generating hydrogen peroxide and toxic halogen derivatives from glucose and sodium iodide by the sequential action of the two enzymes, was cytotoxic to a murine plasmacytoma cell line in vitro (Stanislawski et al., 1989). A second class of targeted enzyme comprises enzymes able to convert relatively non-toxic prodrugs into cytotoxic drugs. A monoclonal antibody-alkaline phosphatase conjugate catalysing the conversion of etoposide phosphate and mitomycin C phosphate into the active parent drugs demonstrated selective anti-tumour effects in a xenograft model superior to the effects of comparable doses of active drug alone (Senter et al., 1988, 1989). Similarly, a monoclonal antibody conjugate made with a Pseudomonas enzyme of unique specificity, carboxypeptidase G2 generating a toxic bis-chloro mustard compound from a much less active glutamyl derivative of the drug, inhibited the growth of tumour xenografts (Bagshawe et al., 1988; Bagshawe, 1989). This approach combines the advantages of pre-localization of a non-toxic antibody conjugate with the catalytic amplification of cytotoxic activity. In contrast with the two-stage targeting of cytotoxic agents by bispecific antibody conjugates, in which the mediation of cytotoxicity is dependent upon localization of the conjugate at the tumour cell surface, enzyme conjugates are catalytically active in the circulation necessitating additional strategies to reduce non-specific prodrug activation (Bagshawe, 1989). LIMITATIONS OF ANTIBODY THERAPY Experimental and clinical studies of antibody therapy have identified a number of limitations of the general approach determined by the nature of the tumour and the target antigen, and by the properties of the antibody and the strategy of targeting (Wawrzynczak & Thorpe, 1986; Dillman, 1987). In humans, antibody binds readily to malignant cells in the circulation but only a small proportion of the total antibody administered intravenously localizes in solid tumour. The factors influencing localization include the anatomical location of the tumour, its vascularity, the level of blood flow, the

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interstitial pressure and the nature of the extracellular matrix. The efficacy of antibody therapy is influenced by the level of antigen expression, its rate and route of internalization, and by whether it can be shed into the circulation or modulated following antibody binding. Many tumour-associated antigens are heterogeneously expressed by tumour cells and are also found on some normal tissues. Immunoglobulins are large protein molecules which extravasate slowly and diffuse poorly in the tissues compared with conventional drugs of low molecular weight. Murine antibodies are immunogenic in humans and the unique idiotypic determinants of any type of antibody may induce a neutralizing immune response. The attachment of other agents to form antibody conjugates may introduce additional complications such as partial inactivation of the antibody or the agent itself, increased immunogenicity, increased size and altered pharmacokinetic behaviour. In the case of two-stage delivery methods, the appropriate doses and the schedule of administration of the two components are key factors. Many problems associated with antibody therapy are being vigorously addressed. Two are worthy of special mention. Firstly, the use of two or more agents in combination to enhance the effectiveness of antibody therapy. Thus, a cocktail of ricin A chain immunotoxins was more effective at inhibiting the clonogenic growth of human breast carcinoma cells than the individual immunotoxins (Yu et al., 1990). Several studies have shown that the growth of tumour in vivo was inhibited more effectively by combination of immunotoxins with therapeutic drugs than by either of the agents independently (Sironi et al., 1984; Weil-Hillman et al., 1987; Pearson et al., 1989a, 1989b; Yokota et al., 1990). Interferons may enhance the anti-tumour effects of immunotoxins either directly, by inducing or increasing the expression of target antigen, as reported in this issue (Chiron et al., 1990), or indirectly, by activating macrophages in vivo (Yokota et al., 1990). By combination treatment, the problems of antigenic heterogeneity and cellular resistance to therapy might be overcome without resorting to the use of immunoconjugates with less selective effects. Secondly, an important development is the new recombinant DNA technology allowing the redesign of therapeutic antibodies. The recent advances include the refashioning of antibodies by genetic transplantation of the complementarity determining regions of a murine antibody into the framework of a human antibody (Hale et al., 1988), the bacterial production of an antigen-binding single-chain Fv protein (Colcher et al., 1990) and the construction of recombinant immunotoxins (Chaudhary et al., 1989). In future, it will be possible to construct antibodies and immunoconjugates with properties optimized for use in therapy. CONCLUSION An effective strategy of antibody therapy must be capable of delivering a potentially beneficial dose of antibody, immunoconjugate or cytotoxic agent to tumour within acceptable levels of general toxicity. The choice of the most appropriate strategy is dictated by the consideration of a complex of factors that are in part poorly understood and whose importance differs from one malignancy to another. An improved understanding of the problems of antibody therapy allied with the imaginative development and exploitation of new strategies and novel

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Strategies in antibody therapy of cancer.

Clin. exp. Immunol. (1990) 82, 189-193 EDITORIAL REVIEW Strategies in antibody therapy of cancer E. J. WAWRZYNCZAK & A. J. S. DAVIES Institute of Ca...
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