Discuss The Effector Functions Of Antibodies Essay Contest

Abstract

Anti‐T‐cell monoclonal antibodies (mAbs) form a unique class of therapeutic agent. Their precise specificity offers tremendous potential for the treatment of autoimmune and inflammatory diseases but also prevents meaningful preclinical animal studies. In particular, adverse reactions to therapy may be unanticipated, and the first administration of a novel T‐cell mAb to a patient thus marks the beginning of a unique experiment. By comparing clinical parameters and laboratory measurements, small‐scale pilot studies can provide detailed information about mAb biology that both predicts and suggests solutions to the complications of therapy. In this essay I illustrate this concept with reference to three specific areas: lymphocyte depletion, mAb immunogenicity and cytokine‐release syndromes. In each case, systematic clinical and laboratory science has improved our understanding of the problem and suggested solutions; most of these solutions have been or are being adopted. Thus, small, open studies are an essential step in the development of novel mAbs, provide an ideal platform for the study of mAb biology, and serve as an early warning system for potential adverse effects.

Monoclonal antibody, Immunotherapy, Effector function, Lymphopenia, Immunogenicity, Humanization, First‐dose reaction, Cytokine release reaction, Mutagenesis.

The 1999 Michael Mason Prize Essay

Animal studies leave little doubt as to the potential therapeutic power of T‐cell‐directed monoclonal antibodies (mAbs) in transplantation and autoimmune disease. Their application can not only prevent illness but, more importantly, halt and reverse ongoing immunopathology. Perhaps the most impressive aspect of their use is that these outcomes can be achieved with relatively brief courses of therapy [1]. The mechanisms underlying such potent effects are not yet entirely clear, but it seems that therapy is associated with the development of regulatory lymphocytes which keep autoreactive cells in check [2].

There are already hints that equally powerful effects may be attainable in man. Thus, over the past 5 yr we have witnessed apparently permanent modulation of severe, refractory human immunopathology following brief courses of mAb therapy [3–6]. In contrast to these anecdotal achievements in vasculitis and ocular disease, however, success has been more limited in commoner conditions, such as rheumatoid arthritis (RA) [7–9]. There are a number of potential reasons for this, which have been well rehearsed [10, 11], and many are currently being addressed by our own group and by others. For example, in ongoing studies we are examining the effects of increasingly intensive regimes of CD4 mAb therapy in RA and, additionally, the need to combat inflammation prior to anti‐T‐cell therapy [12, 13]. Similarly, in a forthcoming study we intend to address the potential importance of CD8 lymphocytes in active RA. However, the major obstacle to successful studies is, paradoxically, the specificity of mAbs. Because of this we cannot simply take a mAb which has been effective in a mouse model of RA and administer it to our patients: it would almost certainly fail to bind the equivalent human target. This is a limitation because we do not understand how mAbs achieve their immunomodulatory effects in animals. Thus, we cannot examine a mAb which is efficacious in animal models and, based on its biological profile, design a similar mAb for human therapy: we do not know which aspects of this profile are important. Until such information becomes available, human mAb therapy will continue along a somewhat pragmatic path: we will test novel agents as they become available, not knowing whether, for example, one CD4 mAb is more or less likely than the next to be an effective immunomodulatory therapy. At present, the only way to find out is to compare them in the clinic. (A potential solution is to test novel mAbs in primates, which share many antigenic specificities with humans, but this approach raises its own ethical issues.)

So, to the topic of this essay. When T‐cell mAbs are administered to laboratory animals they appear extremely safe. For example, one of the prevailing arguments for the relative inefficacy of CD4 mAbs in man is that the doses administered are too small: 1 g of mAb seems a large dose to administer to our patients, yet if we scale up the quantity required to modulate severe immunopathology in mice, we arrive at figures in excess of 100 g. Even so, laboratory mice do not appear to suffer from such massive amounts of treatment, and it has therefore been assumed that these are relatively safe drugs. There are obvious loopholes to this argument (not least the fact that laboratory mice tend not to complain!), and an alternative view might be as follows. If antibodies have evolved through millions of years to become the exquisitely specific, highly efficacious proteins that they are, then they should possess fairly powerful biological effects. It follows that if we infuse large amounts of monospecific mAbs into patients, then perhaps we should expect adverse as well as beneficial outcomes. As with efficacy, however, this cannot be assessed directly in animal studies—in this case not only will the mAb variable (V)‐region fail to recognize its target, but the constant (C)‐region (again highly evolved, and encompassing a variety of natural isotypes and polymorphic allotypes) may not ‘dock’ appropriately with murine effector mechanisms (complement and Fc receptors). This essay focuses on our initial experiences using mAbs for treatment of autoimmune disease and, in particular, on three specific side‐effects: target cell depletion, cytokine release syndromes and immunogenicity. In each case, in vitro models and assays led to suggestions for improving tolerability which have now been incorporated in second‐ and third‐generation agents. The important message is that, to obtain the best results from modern biological therapies, clinical research must be supported by excellent laboratory science. Furthermore, with the appropriate clinical/laboratory interface, much can be learned from small, observational, open studies.

The fate of the target cell

When mAbs were first applied as therapies in animal models of autoimmune disease, depletion of targeted lymphocytes was the order of the day [14]. The rationale was that if an autoreactive immune system could be ablated, a new immune system may develop in its place which would not necessarily share the same autoaggressive characteristics. Indeed, such strategies were highly successful in animal models, although later experiments suggested that non‐depleting mAbs were equally effective [15]. Of note, lymphocyte depletion did not seem to adversely affect animals housed in conventional ‘dirty’ facilities, suggesting that immunosuppression was not a major hazard of therapy. Consequently, one of the first mAbs to be developed as a potential immunomodulator in humans was originally selected because of its promise as a lymphocytotoxic agent [16]. The mAb, directed at an antigen now known as CD52 but at the time as the Campath‐1 antigen (Campath because the mAb was made in the Cambridge University Department of Pathology), was christened CAMPATH‐1 (upper‐case to denote the antibody as opposed to the antigen). CD52 is present on lymphocytes, natural killer (NK) cells and monocytes [17]. The original hybridoma was generated by immunizing a rat with human lymphocytes and so the original mAbs were of rat origin. The rat IgM version (CAMPATH‐1M) was exceptionally potent in complement‐mediated lysis (CML) in vitro, and the rat IgG2b (CAMPATH‐1G) in both CML and antibody‐dependent cell‐mediated cytotoxicity (ADCC, an in vitro assay traditionally used as a surrogate marker for the capacity of a mAb to kill target cells in vivo via Fcγ receptors) [18].

The capacity of CAMPATH‐1 mAbs to kill cells in vivo had already been exploited in the therapy of lymphoreticular malignancies [19], when it was decided to use them to treat autoimmune disease. CAMPATH‐1H, a ‘humanized’ version of the mAb [20] with a human IgG1 Fc region, was first administered to RA patients in June 1991 [21] and trials continued locally and internationally (under the direction of Wellcome and Burroughs Wellcome) until 1994 [22–24]. Placebo‐controlled studies were never performed, and therefore the transient improvement in symptoms associated with therapy were never formally confirmed. As predicted, the mAb was extremely potent at target cell depletion, lymphopenia appearing in peripheral blood with doses as low as 1 mg [22]. The duration of lymphopenia was, however, unexpected and disconcerting. This lasted from months to years and particularly affected the CD4+ subset of peripheral blood T cells (Fig. 1) [25]. At the time, this was attributed to a defect in lymphocyte reconstitution, perhaps intrinsic to the RA disease process itself or related to concurrent or subsequent therapies. Recent evidence suggests that it merely reflected the inability of an involuted adult thymus to permit maturation of marrow‐derived lymphocyte precursors. Thus, it is now recognized that similar kinetics of reconstitution are seen in other situations, such as bone marrow and autologous stem cell transplantation when performed after adolescence [26]. (This is an important observation, given the current trend for autologous stem cell transplantation in RA, which may result in equally dramatic and long‐lasting lymphopenia.)

Subsequent to our work with CAMPATH‐1H, prolonged lymphopenia was also seen with a CD4 mAb, cM‐T412. This was a chimaeric mouse/human mAb, also of hIgG1 isotype, which was employed in a number of controlled and uncontrolled studies in RA [7, 8, 27–30]. cM‐T412‐associated lymphopenia exemplified the uncertainties facing immunotherapists at that time. A number of rodent CD4 mAbs had already been administered to RA patients with variable but always transient lymphocyte depletion [10] and, although a mAb of hIgG1 isotype was expected to deplete more potently, another hIgG1 CD4 mAb did not [11]. Thus, the lack of preclinical testing resulted in some surprising biological outcomes of mAb therapy, many of which were not predictable or readily understandable.

The relevance of prolonged peripheral blood CD4+ lymphopenia in this context, particularly when the synovium remains T‐cell‐replete [31], is unclear. Our own long‐term follow‐up of these patients has failed to identify a high infection risk [32], but in the era of HIV‐1, and in the absence of any clear long‐term effects on the RA disease process, CAMPATH‐1H (and cM‐T412) were dropped as potential therapies for RA. In other circumstances, however, dramatic effects were witnessed in small, uncontrolled studies of CAMPATH‐1H and we continue to use this mAb in the therapy of refractory vasculitis [3, 4, 33], multiple sclerosis [34], various forms of eye disease [5, 6, 35] and occasionally in other conditions [36].

Although CAMPATH‐1H was initially selected as a depleting mAb on the basis of in vitro lymphocytotoxicity, at that time there was little evidence linking in vitro tests such as CML and ADCC with in vivo activities of mAbs. For example, a contemporaneous paper could show no relationship between CD4+ lymphocyte depletion in vivo in mice and CML and ADCC in vitro for a panel of CD4 mAbs [37]. Furthermore, other studies showed that rules generated for one antigen did not necessarily translate to another [38] or to the same antigen at a different density [39], and increasingly population polymorphisms were being identified which might alter mAb biology in vivo [40]. These data, together with the human CD4 experience referred to above, encouraged us to develop a preclinical model that would help us to understand how mAbs deplete target cells in in vivo. We expected that this would help us to generate rules for designing mAbs which were tailor‐made for particular therapeutic scenarios.

Our model was simple [41]. First, using recombinant molecular techniques, we developed a large panel of chimaeric mAbs specific for the mouse CD8 antigen. These shared the same V‐region but possessed a range of wild‐type and mutated C‐regions. Each underwent extensive in vitro testing to characterize its biological activities [41]. They were then administered, in parallel, to groups of thymectomized CBA/ca mice. Their in vivo effects were monitored using flow cytometry to document the number of CD8+ lymphocytes remaining in peripheral blood at subsequent time points. Because the animals had been thymectomized, they were unable to reconstitute lysed cells, enabling us to differentiate between transient sequestration and cytotoxicity. (Ironically, the long‐term depletion seen in thymectomized mice paralleled the effects of CAMPATH‐1H and cM‐T412 in patients; as suggested above, in humans the thymus involutes after adolescence, resulting in a relative ‘physiological’ thymectomy.) We selected the CD8 antigen for these experiments in the knowledge that this was a sensitive mAb target in mice [42] and because limited quantities of chimaeric mAb were likely to be available from our small‐scale laboratory cultures of transfectomas.

Our strategy was rewarded when we demonstrated that as little as 5 μg of chimaeric mAb could lead to lasting depletion of CD8+ peripheral blood lymphocytes. Both rat and human isotypes interacted with mouse effector systems, resulting in efficient depletion of cells. In our initial experiments, rat IgG1 (rIgG1), rIgG2b, human IgG1 (hIgG1), hIgG2, hIgG3 and hIgG4 were all potent depleters, whereas rIgG2c, hIgA and hIgE were impotent and rIgG2a had an intermediate potency (Fig. 2). It was surprising that isotypes that were very poor at harnessing in vitro effector activities (hIgG2, hIgG4) were so potent in vivo and, to an extent, this validated the need for an in vivo model. Equally, however, this provoked criticisms over the value of a heterologous system (human and rat mAbs administered to mice) and raised the possibility that our results were artefactual. We therefore dissected the system further. We demonstrated that an aglycosyl variant of hIgG1, created by site‐directed mutagenesis of amino acid residue 297, no longer depleted [41]. The N‐linked carbohydrate attached to residue 297 of IgGs was known to be essential for complement activation and Fcγ receptor (FcγR) binding [43], suggesting that our initial results were a genuine reflection of mAb–effector mechanism interactions. We then showed that a mutant of hIgG1 that could not bind Clq still depleted, even in mice lacking the C3 component of complement, indisputably excluding complement as an effector pathway in this model [41]. Finally, we demonstrated that mutations within the FcγR binding motif (residues 233–238 in the mAb lower hinge) completely arrested depletion by hIgG1 and hIgG4, supporting a critical role for FcγRs in this model (Fig. 3). In contrast to depleting mAbs, these mutants ‘coated’ CD8+ lymphocytes for several days [44]. We repeated this work using wild‐type and mutant mouse IgG2b (mIgG2b) mAbs, confirming the importance of FcγR interactions and the redundancy of complement in a completely homologous system [44]. Although we were unable to improve the depleting potency of mIgG2b by enabling it to bind the mouse high‐affinity FcγRI, removing its ability to bind mouse FcγRII significantly impaired its ability to deplete cells (Fig. 4).

The model supported our initial hypothesis that in vivo mAb effector function could not necessarily be predicted from in vitro tests. Consequently, no therapeutic mAb should be ascribed particular in vivo biological activities until it has been administered to at least a few patients. This is illustrated by our data from a small study of an hIgG4 version of CAMPATH‐1H [45]. In vitro data suggested that a mAb of this isotype would not deplete but our murine work suggested otherwise. We therefore designed a study in which IgG4 CAMPATH‐1H was administered to a small number of subjects with RA. We witnessed significant depletion in all patients, possibly related to circulating mAb levels (Fig. 5), and presumably mediated by the weak affinity of this isotype for human FcγRI (hIgG4 does not activate complement). It is pertinent to note that a number of therapeutic mAbs are currently being produced with an IgG4 isotype on the assumption that they will not deplete. As a consequence of the above data, however, our own current work focuses on the use of aglycosyl and non‐FcγR‐binding Fc‐mutated mAbs when depletion is an undesirable biological activity.

Fig. 1.

Long‐term lymphopenia following therapy with CAMPATH‐1H. Forty‐one patients received a total dose of 100–400 mg of CAMPATH‐1H over 5 or 10 days. The figure illustrates peripheral blood lymphocyte subsets at various time points after therapy. There was no difference between dosing cohorts and data were therefore pooled. *CD4 (P=0.0001 at day 178) and CD8 (P=0.03 at day 178) counts were different from baseline at all time points. CD19 was different from baseline to day 87 (P=0.03). CD14 was different from baseline to day 31 (P=0.0001). CD16 was different from baseline at day 3 (P=0.0001). Two‐sample t‐test. From [24].

Fig. 1.

Long‐term lymphopenia following therapy with CAMPATH‐1H. Forty‐one patients received a total dose of 100–400 mg of CAMPATH‐1H over 5 or 10 days. The figure illustrates peripheral blood lymphocyte subsets at various time points after therapy. There was no difference between dosing cohorts and data were therefore pooled. *CD4 (P=0.0001 at day 178) and CD8 (P=0.03 at day 178) counts were different from baseline at all time points. CD19 was different from baseline to day 87 (P=0.03). CD14 was different from baseline to day 31 (P=0.0001). CD16 was different from baseline at day 3 (P=0.0001). Two‐sample t‐test. From [24].

Fig. 2.

A comparison of chimaeric CD8 mAbs in vivo. mAb (50 μg) was administered to thymectomized mice via a tail vein in three divided doses (days 1–3). The figure shows the percentage of CD8+ peripheral blood lymphocytes (PBL) remaining at subsequent time points. Each line represents an individual mouse. hIgG1–4, rIgG1 and rIgG2b (including ‘parental’ rIgG2b mAb YTS 169.4) caused potent and rapid depletion. hIgA2 and hIgE were inactive, and rIgG2a was intermediate in potency. From [41]. Copyright 1992. The American Association of Immunologists.

Fig. 2.

A comparison of chimaeric CD8 mAbs in vivo. mAb (50 μg) was administered to thymectomized mice via a tail vein in three divided doses (days 1–3). The figure shows the percentage of CD8+ peripheral blood lymphocytes (PBL) remaining at subsequent time points. Each line represents an individual mouse. hIgG1–4, rIgG1 and rIgG2b (including ‘parental’ rIgG2b mAb YTS 169.4) caused potent and rapid depletion. hIgA2 and hIgE were inactive, and rIgG2a was intermediate in potency. From [41]. Copyright 1992. The American Association of Immunologists.

Fig. 3.

hIgG1 and hIgG4 mutated in the FcγR‐binding motif are impotent in vivo. Groups of four thymectomized mice were administered the mAbs shown on day 0. Depletion of CD8+ peripheral blood lymphocytes (PBL) was measured on day 14 (shown as mean±S.D.). The data are pooled from three experiments. See also Table 2. From [44]. Copyright 1998. The American Association of Immunologists.

Fig. 3.

hIgG1 and hIgG4 mutated in the FcγR‐binding motif are impotent in vivo. Groups of four thymectomized mice were administered the mAbs shown on day 0. Depletion of CD8+ peripheral blood lymphocytes (PBL) was measured on day 14 (shown as mean±S.D.). The data are pooled from three experiments. See also Table 2. From [44]. Copyright 1998. The American Association of Immunologists.

Fig. 4.

mIgG2b depletes via a FcγRII‐dependent mechanism. Groups of four thymectomized mice were administered the mAbs shown. Depletion of CD8+ peripheral blood lymphocytes (PBL) was measured on day 14 (shown as mean±S.D.). The data are pooled from two experiments. Removing the C1q‐binding motif or enabling binding to mFcγRI does not alter depleting potency (groups D–L). Removing the mFcγRII‐binding motif reduces depleting potency (groups M–O). From [44]. Copyright 1998. The American Association of Immunologists.

Fig. 4.

mIgG2b depletes via a FcγRII‐dependent mechanism. Groups of four thymectomized mice were administered the mAbs shown. Depletion of CD8+ peripheral blood lymphocytes (PBL) was measured on day 14 (shown as mean±S.D.). The data are pooled from two experiments. Removing the C1q‐binding motif or enabling binding to mFcγRI does not alter depleting potency (groups D–L). Removing the mFcγRII‐binding motif reduces depleting potency (groups M–O). From [44]. Copyright 1998. The American Association of Immunologists.

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