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Experimental Therapeutics |
Departments of Biochemistry and Molecular Biology, Seattle Genetics, Inc., Bothell, Washington 98021
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CD40 is a target of significant potential for the treatment of B-lineage hematological malignancies as well as certain carcinomas. This Mr 45,000–50,000 integral membrane glycoprotein was originally found on bladder carcinoma cells and later detected on both normal and malignant B cells (8) . Subsequently, CD40 has been identified on a variety of other cell types including dendritic cells, monocytes, thymic epithelial cells, endothelial cells (9 , 10) , and on carcinomas of the lung, colon, and breast (11) . CD40 is a member of the TNF receptor superfamily and plays an important role in the growth, differentiation, and isotype switching of normal B cells (9) . Importantly, ligation of CD40 via mAbs can result in inhibition and cell death on neoplastic B cells (12) .
As a target for mAb-based therapy, CD40 complements CD20 and may have several advantages over CD20. Like CD20, CD40 is highly expressed in B-cell malignancies including leukemias, lymphomas, and Hodgkin’s disease (13 , 14) . Importantly, CD40 is found on a higher percentage of multiple myelomas compared with CD20 (15) . Unlike CD20, CD40 is also highly expressed on the surface of a variety of carcinomas, increasing the potential therapeutic application of mAbs targeted to CD40. In a recent study comparing the effects of an anti-CD20 and a ligand blocking anti-CD40 mAb in human B-cell lymphoma xenografted SCID mice, Funakoshi et al. (16) demonstrated that although both mAbs possessed potent antitumor activity in the presence of Fc receptor-bearing effector cells, the mAb targeted to CD40 was more efficacious when these effector cells were depleted.
In this study, we have examined the in vitro and in vivo antitumor activity of mAb SGN-14, an agonistic antihuman CD40 mAb. SGN-14, originally called S2C6, was the first mAb used to identify CD40 on bladder carcinoma cells (17) . We show that SGN-14 enhances the interactions between CD40 and its ligand, CD40L. In vitro, this enhancement resulted in stimulation of primary B cells and modest antitumor activity in the presence of SGN-14 and CD40L. In vivo, through the use of human lymphoma xenografted SCID mice, we demonstrate that this antibody has significant antitumor activity even when the activity of natural killer cells has been inhibited. Additionally, SGN-14 was effective in treating SCID mice xenografted with human multiple myeloma.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recombinant human IL-4 was purchased from Biosource (Camarillo, CA); FITC-labeled recombinant human CD40 ligand (CD40L), produced as a fusion protein with murine CD8 and was obtained from Research Diagnostics, Inc. (Flanders, NJ); soluble CD40-immunoglobulin, consisting of the extracellular domain of human CD40 fused to a human immunoglobulin tail, and G28-5 mAb were obtained from Bristol-Myers Squibb (Princeton, NJ); M3 mAb was obtained from Genzyme (Cambridge, MA); FITC-labeled F(ab')2 goat antihuman immunoglobulin was purchased from Jackson Immunoresearch (West Grove, PA); and anti-asialo GM1 was purchased from Wako Chemicals (Richmond, VA).
Antibody Preparation.
The SGN-14 hybridoma, originally called S2C6 (17)
, was
cultured at 37°C in complete HSFM media (Life Technologies, Inc.)
supplemented with 100 units/ml penicillin and 100 µg/ml streptomycin.
When the cells reached a viability of 
50%, the culture was harvested
by centrifugation, and the supernatant was collected by filtration
through a 0.2 µm filter. Subsequently, the supernatant was diluted
1:1 with 3 M NaCl, 0.1 M
NaBO4 (pH 8.5) and loaded onto a Pierce GammaBind
Sepharose column (Pierce, Rockford, IL), washed with PBS, and eluted
with 0.1 M citrate (pH 3.0). Immediately upon elution, the
mAb was neutralized with 1 M Tris-HCl (pH 8.0) and
subsequently dialyzed into PBS and filter sterilized. SGN-14
preparations were verified as >99% monomeric by size exclusion
chromatography and free of detectable endotoxin by LAL assay
(BioWhittaker, Walkerville, MD) for use in these studies.
B-Cell Proliferation Assay.
Human peripheral blood B cells were thawed and incubated in 96-well
tissue culture plates at 1 x 105
per well in IMDM media plus 10% FBS in the presence of 5 ng/ml
recombinant human IL-4 and various dilutions of the anti-CD40 mAbs
SGN-14, G28-5, and M3. As a control, cells were incubated with IL-4 and
a control mAb (anti-Pseudomonas exotoxin) EXA2-1H8. The
plates were incubated at 37°C for 3 days and then pulsed for 16
h with 0.5 µCi [3H]thymidine/well. Cells were
harvested onto 96-well glass fiber filters using a Filtermate 196
Harvester (Packard Instruments, Meriden, CT), combined with
scintillation fluid, and the extent of
[3H]thymidine incorporated into nascent DNA was
measured by liquid scintillation counting in a Topcount LSC (Packard
Instruments, Meriden, CT).
To evaluate B-cell proliferation in the presence of CD40L, BMS-2 cells were used as CD40L stimulator cells. B cells and IL-4 were initially combined with BMS-2 cells (2.5 x 104 per well), followed immediately by the addition of the anti-CD40 mAbs. To eliminate proliferation of the stimulator cells, BMS-2 cells were treated with mitomycin C, 50 µg/ml in PBS for 20 min at 37°C, followed by three washes in PBS, prior to combining with B cells. mAbs were titrated with either a fixed concentration of stimulator cells, or stimulator cells were titrated with a fixed concentration of mAb.
CD40/CD40L Binding Assay.
To evaluate the effect of anti-CD40 mAbs on CD40 binding to CD40L
expressed on T cells, BMS-2 cells were used as target cells. BMS-2
cells were adjusted to a density of 2 x
107/ml in 50-µl samples, and binding was
performed in RPMI 1640 + 10% FBS. CD40-immunoglobulin (25
µg/ml; saturating level) was preincubated for 1 h on ice with
increasing levels of either mAb SGN-14, G28-5, M3, or an irrelevant mAb
to Pseudomonas exotoxin EXA2–1H8, as an isotype control,
prior to adding to the BMS-2 cells for an additional 1 h on ice.
CD40-immunoglobulin binding to BMS-2 cells was then detected by the
addition of FITC-labeled antihuman immunoglobulin, and the resultant
binding was evaluated using a FACScan flow cytometer (Becton Dickinson,
San Jose, CA).
To evaluate the effect of anti-CD40 mAbs on CD40L binding to human B cells, Ramos cells were used as a target for the binding of FITC-labeled CD40L. Ramos cells (5 x 105) were preincubated for 1 h on ice with increasing levels of either mAb SGN-14, G28-5, M3, or control mAb EXA2–1H8, prior to adding to the FITC-CD40L for an additional 30 min on ice. Cells were washed three times with complete media, and the resultant binding was evaluated by flow cytometry.
In Vitro Growth Inhibition.
HS Sultan or Ramos cell lines were cultured in RPMI 1640 media
containing 10% FBS at a density of 1 x
104 cells/well of 100 µl in 96-well
flat-bottomed plates. Increasing concentrations of SGN-14 or control
mAb were added, and cell viability was determined at 96 h by a
tetrazolium viable dye assay, as described previously
(19)
. To evaluate the effect in combination with CD40L,
this assay was also carried out in the presence of nonproliferating
CD40L-expressing BMS-2 cells at varying ratios and increasing
concentrations of mAb. To block their proliferation, CD40L stimulator
cells were pretreated with mitomycin C as described above.
In Vivo SCID Mouse Studies.
Female CB-17 SCID mice (Taconic, Germantown, NY) were 6–8 weeks of age
at the initiation of all studies. Mice were injected through the tail
vein with 1 x 106 cells on day 0,
and therapy with SGN-14 or control mAb was initiated on the indicated
days. mAbs were administered s.c. with injections given every 4 days
for a total of five injections. In some studies, mice were treated i.v.
with anti-asialo GM1, 200 µl of a 1:10
dilution, as described previously (12)
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This is in contrast to a previous study that indicated
that SGN-14 (S2C6) inhibited the binding of soluble CD40 to
membrane-bound CD40L (22)
. A similar titration with the
antagonistic mAb M3 blocked CD40/CD40L binding in a dose-dependent
manner whereas mAb G28-5 showed little effect (Fig. 1A
).
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). Conversely, both mAbs G28-5 and M3
inhibited in a dose-dependent manner the binding of CD40L to CD40 on B
cells.
SGN-14 and CD40L Costimulate Primary B-Cell Proliferation.
It has been demonstrated previously that agonistic anti-CD40 mAbs,
including SGN-14 (S2C6), in combination with IL-4 will costimulate the
proliferation of human B cells in culture (23)
. To confirm
the agonistic activity of mAb SGN-14, human peripheral blood B cells
were incubated in the presence of 5 ng/ml IL-4 and increasing
concentrations of either SGN-14, mAb M3, mAb G28-5, or EXA2–1H8, an
isotype matched non-binding control mAb. As shown in Fig. 2A
, in the presence of IL-4, all three anti-CD40 mAbs
stimulated primary B-cell proliferation in a dose-dependent manner. It
should be noted that preparations of SGN-14 that contained varying
levels of aggregate gave greater levels of stimulation than monomeric
SGN-14 (data not shown). Even low levels of aggregate, as little as
2%, greatly enhanced the stimulatory activity, and care was taken to
make certain that only monomeric SGN-14 was used in these studies. In
parallel studies done in the absence of IL-4, SGN-14, G28-5, and M3
also stimulated the growth of peripheral B cells, although under these
conditions the maximum level of stimulation for each was 
3-fold less
than that seen in the presence of IL-4 (data not shown). As expected,
control mAb did not provide any stimulation of B-cell growth, either in
the absence or presence of IL-4.
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).
In contrast, in the presence of 30 ng/ml SGN-14, B-cell proliferation
increased in a dose-dependent manner with increasing numbers of BMS-2
cells (Fig. 2B
). Although G28-5 provided some stimulation in
the absence of CD40L, the addition of CD40L-expressing cells only
nominally increased B-cell proliferation (1.3-fold) over the level seen
with G28-5 alone. M3, which showed the greatest proliferative response
of the three mAbs on their own, demonstrated little additional response
with the addition of the CD40L-expressing cells. This cooperative
stimulation between SGN-14 and BMS-2 cells expressing high levels of
CD40L was not seen using parental Jurkat cells expressing low levels of
CD40L (data not shown).
In a variation of this assay, peripheral blood B cells and
mitomycin-treated BMS-2 cells were combined at a fixed ratio of four B
cells to one T cell (4:1) and incubated with a titration of anti-CD40
mAbs (Fig. 2C
). Low level SGN-14 was significantly more
active at inducing B-cell proliferation in combination with CD40L than
by itself. In the presence of CD40L-expressing cells, the highest
concentration of SGN-14 (10 µg/ml) increased B-cell proliferation by
>5-fold over that seen with SGN-14 alone. In contrast, proliferation
of primary human peripheral B cells increased by a maximum of 2-fold
with mAb G28-5 when combined with CD40L cells and <2-fold with mAb M3
when combined with CD40L cells compared with the respective mAb alone.
Taken together, these data indicate that SGN-14 can promote the
interaction between CD40 and CD40L, functionally resulting in a
significant increase in the degree of primary B-cell proliferation.
In Vitro Growth Inhibition Activity of SGN-14.
Ligation of CD40 on normal B cells is essential for activation, whereas
its ligation on malignant B cells can inhibit proliferation
(12)
. Having observed that SGN-14 and CD40L cooperate in
inducing normal B-cell proliferation, we next investigated the effect
of these agents on neoplastic B-cell lines. HS-Sultan and Ramos
non-Hodgkin’s lymphoma cell lines were cultured with increasing
concentrations of SGN-14, M3, or a nonbinding control mAb, either in
the absence or presence of nonproliferating, mitomycin C-treated, BMS-2
cells added at a ratio of 4:1 (B cell:BMS-2). Cell viability was
determined at 96 h after treatment by the tetrazolium dye assay
(19)
. This assay was selected because it measures cell
viability, compared with thymidine incorporation, which does not
discriminate between cytostasis and cytotoxicity. In the absence of
CD40L+ cells, neither SGN-14 nor M3 had an effect
on the growth of either HS-Sultan or Ramos cells. In contrast, SGN-14
inhibited the growth of these cell lines in a dose-dependent manner in
the presence of the CD40L-expressing cells (Fig. 3
). The inhibition of growth by SGN-14 became evident at concentrations
>100 ng/ml with a maximum of 25% inhibition at 10 µg/ml. Under
these conditions, a maximum of 10% inhibition was seen with mAb M3
combined with CD40L+ cells.
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). SGN-14 administered at 1 mg/kg/injection every 4 days for a total of
five injections, starting either 1 or 5 days after tumor implantation,
conferred a significant survival advantage in both disease models.
SGN-14 was most effective in the Ramos model, where five of five
animals receiving SGN-14 starting on day 1 after implant and four of
five animals receiving it beginning on day 5 remained asymptomatic for
the duration of the study (120 days; Fig. 4A
). In the
HS-Sultan-bearing animals, three of five mice receiving treatment on
day 1 and two of five mice receiving treatment on day 5 survived for
the length of the study (Fig. 4B
). Importantly, even in mice
that succumbed to these diseases, treatment with SGN-14 significantly
delayed the onset of disease compared with untreated animals or those
that received control mAb.
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, all of the anti-asialo
GM1-treated mice bearing Ramos tumor cells and
receiving SGN-14 therapy starting on day 5, and four of five animals
starting SGN-14 treatment on day 1, survived for the duration of the
experiment without developing any signs of disease. In a subsequent
Ramos study aimed at maximizing NK depletion, anti-asialo
GM1 was administered prior to each dose of
SGN-14. This regimen yielded similar SGN-14 efficacy to that described
above with 90% symptom-free survival for the duration of the study
(data not shown). Thus, in the Ramos model, blunting of host NK
activity did not detract from the antitumor efficacy of SGN-14. With
the HS-Sultan tumor model (Fig. 4D
), three of five animals
receiving anti-asialo GM1, followed by SGN-14
therapy starting on day 1, remained asymptomatic. This was comparable
with results in mice that did not receive the anti-asialo
GM1 pretreatment. When initiation of SGN-14
treatment was delayed until day 5, all of the mice that were pretreated
with anti-asialo GM1 succumbed to the disease by
day 105, with a mean paralysis time of 65 days. Under these conditions,
SGN-14 still offered significant efficacy compared with untreated
controls.
Antitumor Activity of SGN-14 in Multiple Myeloma Xenografted SCID
Mice.
In addition to its expression on non-Hodgkin’s lymphoma, CD40 is also
highly expressed in multiple myeloma. To determine whether SGN-14 was
efficacious in treating multiple myeloma, SCID mice were implanted i.v.
with IM-9 multiple myeloma cells. As with the non-Hodgkin’s xenograft
models, all of the untreated IM-9-bearing SCID mice developed a
disseminated disease, primarily manifested by hind-limb paralysis and
motor ataxia, and had to be sacrificed within 50 days of tumor
implantation (Fig. 5
). Treatment with SGN-14 at 1 mg/kg, every 4 days for a total of five
injections, starting either 1 or 5 days after tumor inoculation,
significantly increased the survival of all of the animals, with three
of five remaining symptom free for 120 days after tumor implant in each
group.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It has been shown previously that either soluble trimeric CD40 ligand or antagonistic mAbs that block ligand/receptor interaction inhibit the growth of B-lineage malignancies (12 , 30) and CD40-expressing carcinomas (31) . We show here that the agonistic anti-CD40 mAb, SGN-14, has potent antitumor activity against two aggressive human B-lymphoma cell lines, Ramos and HS-Sultan, as well as IM-9 multiple myeloma, in xenografted SCID mice. Left untreated, mice succumbed to disease without exception. In contrast, 90% of the Ramos and 50% of the HS-Sultan xenografted mice survived for the duration of the study, 120 days, after treatment with 1 mg/kg SGN-14. At the time of sacrifice, these surviving mice did not show any signs of disease. Because SGN-14 is a murine antibody and is thus able to engage host effector functions to eliminate tumor cells, we investigated the significance of host effector cells in antitumor activity by evaluating SGN-14 efficacy after blunting of host NK cells through the use of anti-asialo GM1. Pretreatment with anti-asialo GM1 did not affect the activity of SGN-14 against Ramos xenografts, although it did impact long-term survival in the HS-Sultan model. Thus, although NK activity appears to play a role in the efficacy of SGN-14 in vivo, as demonstrated in the HS-Sultan model, the mAb itself possessed significant antitumor activity in the absence of these cells. Although it is informative to minimize the effect of host effector functions in xenograft models such as these, the ability to recruit effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity, could help to increase the effectiveness of mAbs, such as SGN-14, in a clinical setting.
It is unclear why SGN-14 possesses potent antitumor activity in vivo and yet has only modest growth-inhibitory activity on these same cell lines in vitro. Other recent studies have had difficulty correlating the in vivo efficacy of mAbs with their relatively weak in vitro cell killing. In comparing the therapeutic effects of mAbs directed against a variety of surface antigens, including IgM, CD19, CD22, CD40, CD74, and MHC class II, as well as anti-idiotypic antibodies expressed on mouse B-cell lymphomas in vivo, Tutt et al. (32) demonstrated that the in vitro activity of these antibodies did not correlate with their activities in vivo. In fact, the in vivo activity appeared to be a function of the ability of the mAb to cross-link and signal via its target receptor. Additionally, other mAbs against CD40 that showed little cytotoxic activity in vitro, including the antibody M3 used in the present study, have had potent antitumor activity in vivo (12) . Despite its potent antitumor activity in vivo, SGN-14 inhibited the growth of B-lymphoma cell lines in vitro by a maximum of 25%, and this was accomplished only in the presence of CD40L.
Because both soluble trimeric CD40L and SGN-14 possess antitumor activity in vivo and these agents cooperate to inhibit the growth of B-lymphoma cells in vitro, it will be interesting to evaluate the combined effect of ligand and mAb in CD40-expressing models of human cancer. This is particularly relevant because increased levels of soluble CD40L have been reported in some patients with B-cell malignancies (33) . The mechanism by which SGN-14 augments the interaction of CD40L with CD40 is unclear. As with other TNF receptor family members, signaling via CD40 likely results from receptor and subsequent TRAF multimerization after interaction with the trimeric ligand (34) . It is possible that SGN-14 induces a conformational change that stabilizes CD40 multimerization in the presence of CD40L. Alternatively, in the presence of ligand, SGN-14 may induce aggregation of ligand/receptor trimers. It has been shown that CD40 mutants defective in multimerization can be driven to TRAF-mediated signaling by aggregation (29) .
The evolution of mAbs as therapeutics has taken many years to reduce to practice. mAb SGN-14 (S2C6) was originally characterized some 15 years ago as recognizing a tumor antigen displayed on bladder cell carcinoma, Bp50 (2) , prior to its recognition as a key activating receptor on B cells. This report describes, for the first time, the ability of this mAb to eliminate B-cell disease in animal models. Although previous reports have shown that mAbs targeted to CD40 can be efficacious in treating mice with disseminated non-Hodgkin’s lymphoma, the results presented here demonstrate that SGN-14 is effective in treating models of both non-Hodgkin’s lymphoma and multiple myeloma and suggest that SGN-14 and other anti-CD40 mAbs should be evaluated in anti-cancer clinical trials.
As with other mAb-directed antitumor therapies, the expression of the CD40 on normal tissue in addition to neoplasia must be taken into account as clinical trials using SGN-14 are designed. CD40 is expressed on endothelial cells and other normal tissues. It is fortunate that antibodies against human CD40 cross-react with monkey CD40, which will allow for extensive toxicological analysis in non-human primates. We have evaluated previously the toxicity of a single-chain immunotoxin targeted to human CD40 in cynomolgus monkeys and found that the immunotoxin was well tolerated with no signs of vascular toxicity (25) . In the present study, soluble SGN-14 had little effect on the growth of normal B cells. We have also seen that SGN-14 has no effect on the growth of CD40-expressing fibroblasts in vitro.4 Taken together, these suggest that SGN-14 may be well tolerated in a clinical setting.
Currently, efforts are under way to generate engineered forms of SGN-14 for potential evaluation in clinical trials in CD40-expressing malignancies. The ability to target multiple myeloma, in addition to lymphoma, presents a significant opportunity for a chimeric or humanized form of SGN-14 because there are currently no durable therapeutic options for patients with multiple myeloma, and CD40 is one of just a few antigens that are available as targets for this disease (15) . There is also the possibility that this mAb may be useful in treating CD40-expressing carcinomas, although the in vitro and in vivo effects of SGN-14 on solid carcinomas have not yet been examined.
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FOOTNOTES |
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1 Present address: Department of Immunology,
Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box
4000, Princeton, NJ 08543. 
2 To whom requests for reprints should be
addressed, at Department of Biochemistry, Seattle Genetics, Inc., 22215
26th Avenue SE, Bothell, WA 98021. Fax: (425) 489-8888; E-mail: awahl{at}seagen.com
3 The abbreviations used are: mAb, monoclonal
antibody; TNF, tumor necrosis factor; SCID, severe combined
immunodeficient; IL, interleukin; FBS, fetal bovine serum; NK, natural
killer; TRAF, TNF receptor-associated factor; FACS,
fluorescence-activated cell sorting.
4 A. F. Wahl, unpublished observations.
Received 11/23/99. Accepted 4/10/00.
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REFERENCES |
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interferon. Blood, 73: 651-661, 1989.This article has been cited by other articles:
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  C.-L. Law, K. A. Gordon, J. Collier, K. Klussman, J. A. McEarchern, C. G. Cerveny, B. J. Mixan, W. P. Lee, Z. Lin, P. Valdez, et al. Preclinical Antilymphoma Activity of a Humanized Anti-CD40 Monoclonal Antibody, SGN-40 Cancer Res., September 15, 2005; 65(18): 8331 - 8338. [Abstract] [Full Text] [PDF]
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), G28-5
(
), M3 (
), or a nonbinding control mAb EXA2-1H8 (X).
) from
A is included for reference of scale.
), or
received 1 mg/kg SGN-14 starting 1 (