Innovations That Influence the Pharmacology of Monoclonal Antibody Guided Tumor Targeting1

(CANCER RESEARCH (SUPPL.) 50, 820s-827s. Feburary 1, 1990] Innovations That Influence the Pharmacology of Monoclonal Antibody Guided Tumor Targeting1

Jeffrey Schlom,2 Patricia Horan Hand, John W. Greiner, David Colcher, Shashi Shrivastav, Jorge A. Carrasquillo, James C. Reynolds, Steven M. Larson,3 and Andrew Raubitschek

Laboratory1of Tumor Immunology and Biology [J. S., P. H. H., J. W. G., D. C., S. S.J, Department of Nuclear Medicine, Clinical Center fJ. A. C., J. C. R., S. M. LJ, and Radiation Oncology Branch [A. R.], National Cancer Institute, and NIH, Bethesda, Maryland 20892

Abstract regulate the expression of specific tumor associated antigens such as carcinoembryonic antigen (CEA) or TAG-72 on the Tumor targeting by monoclonal antibodies (MAbs) can be enhanced surface of carcinoma cells and thus increase MAb tumor bind by (a) increasing the percentage of injected dose taken up by the tumor ing; (b) the intracavitary administration of MAbs. Recent stud and/or (b) increasing the tumor:nontumor ratios. Several groups have demonstrated that one can increase tumor to nontumor ratios by the use ies have demonstrated that when radiolabeled MAb B72.3 is of antibody fragments or the administration of second antibodies. Several administered i.p. to patients with carcinoma of the peritoneal other modalities are also possible: (a) the use of recombinant interferons cavity, it localizes tumor masses with greater efficiency than to up-regulate the expression of specific tumor associated antigens such does concurrent i.v. administered antibody. Studies involving as carcinoembryonic antigen or TAG-72 on the surface of carcinoma cells the comparative pharmacology of intracavitary administration and thus increase MAb tumor binding has proved successful in both in of radiolabeled MAb in patients and several animal models will vitro and in vivo studies; (b) the intracavitary administration of MAbs. be discussed; (c) it has been reported that prior exposure of Recent studies have demonstrated that when radiolabeled B72.3 is ad hepatoma to external beam radiation will increase radiolabeled ministered Â¡.p.to patients with carcinoma of the peritoneal cavity, it MAb tumor targeting. We and others have not been able to localizes tumor masses with greater efficiency than does concurrent i.v. duplicate this phenomenon with a human colon cancer xeno administered antibody. Studies involving the comparative pharmacology of intracavitary administration of radiolabeled MAb in patients and graft model and radiolabeled MAbs to two different colon several animal models will be discussed; (c) it has been reported that carcinoma associated antigens. The possible reasons for these prior exposure of hepatoma to external beam radiation will increase differences will be discussed; (d) the cloning and expression of radiolabeled MAb tumor targeting. We and others have not been able to recombinant MAbs with human constant regions and subse duplicate this phenomenon with a human colon cancer xenograft model quent size modification constructs will undoubtedly alter the and radiolabeled MAbs to two different colon carcinoma associated pharmacology of MAb tumor binding. antigens. The possible reasons for these differences will be discussed; (September 8-10, 1988, Princeton, NJ. in experimental models using established human carcinoma cell 2To whom requests for reprints should be addressed, at Laboratory of Tumor lines and in biopsies prepared from in situ carcinoma lesions Immunology and Biology, Bldg. 10, Rm. 8B07, 9000 Rockville Pike, Bethesda, (10, 11). Data are available that demonstrate that, within pri MD 20892. 3Present address: Nuclear Medicine Service, Memorial Sloan Kettering Cancer mary and metastatic human carcinomas, not all of the cells may Center, New York, NY 10021. 4The abbreviations used are: MAb, monoclonal antibody; TAG, tumor asso express a given tumor antigen. Although tumor cell heteroge ciated glycoprotein; rHuIFN, recombinant human interferon; %ID/kg, percentage neity can be defined according to a large number of cellular of injected dose of MAb/kg; RI, radiolocalization index. criteria (i.e., cell size, metastatic ability), the heterogeneity of 820s

Table 1 Parameters of MAb guided tumor localization and therapy responsiveness of a human tumor Cell line to the ability of rHu- 1. Number of antigen molecules per cell surface IFN-aA to augment surface tumor antigen expression in vivo; 2. Number of cells expressing the reactive antigen in the tumor mass (b) have shown the advantage of a delivery system to administer 3. Size of the tumor mass 4. Fate of antigen-antibody complex rHu-IFN that results in sustained long-term plasma levels; and a. Stability on cell surface also (c) have provided a basis to investigate the relationship b. Internalization c. Capping between in vivo plasma levels and the resultant amount of in d. Shedding vivo localization of a MAb to the tumor site. 5. Degree of vascularization of the tumor Recent studies have demonstrated that recombinant interfer 6. Degree of infiltration and necrosis in the tumor mass 7. Presence and reactivity of circulating antigen in the blood ons a (clone A), 0-ser, and 7 can all up-regulate the expression 8. Duration of MAb binding to cell surface of some (but not all) tumor associated antigens including car- 9. Isotype of immunoglobulin (IgG subtypes or IgM) cinoembryonic antigen and TAG-72 (22). Many of these are 10. Species of immunoglobulin: murine, human, recombinant/chimeric 11. Whole immunoglobulin or fragments: Fab, Fab'. F(ab')2 summarized in Table 2. Recent studies by Rosenblum et al. 12. Clearance of MAb from blood (MAb metabolism) (26) have also shown that interferons can up-regulate tumor a. Excretion b. Reticuloendothelial system targeting of radiolabeled MAbs in a clinical trial. Preclinical c. Administration of second antibody studies have also demonstrated that recombinant interferons 13. Dose of MAb used can both increase the amount of tumor antigen expressed by a 14. Route of inoculation of MAb (i.v., i.p., intralymphatic. intraarterial) 15. Development of a human immune response to the administered MAb given tumor cell and increase the percentage of cells within the a. To constant region tumor cell population that express the antigen. Thus, antigenic b. Antiidiotype heterogeneity of tumor masses can perhaps be dealt with using If radiolabeled MAb is used one or a combination of (a) mixtures of MAbs, (b) radionuclides 16. Ability of MAb to be labeled with specific radionuclide that can kill several cell diameters, and (c) the use of recombi 17. Specific activity of radiolabeled MAb 18. Affinity of radiolabeled MAb nant interferons. 19. Depth of tumor from body surface (for tumor localization) 20. Time of scanning (for tumor localization) 21. Choice of radionuclide Intracavitary Administration of MAbs 22. Method of linkage of radionuclide to MAb a. Metabolism of MAb-radionuclide complex b. Catabolism of MAb-radionuclide Intracavitary disease such as pleural effusions, ascites, peri 23. Dose fractionation of administered MAb toneal implants, or intrathecal tumors are fairly common man ifestations of carcinoma. For example, the peritoneal cavity is the primary disease site of ovarian carcinoma, and mÃ©tastases antigen expression and its potential impact on MAb use for originating from the breast and colon. Administration of diag tumor detection and/or therapy will be discussed here. nostic tumor targeting agents and therapeutic agents via an rHu-IFNs are potent immunomodulatory compounds capa intracavitary route provides the theoretical advantages of (a) ble of altering the antigen phenotype of a variety of human cells increasing the concentration of the agent present at the tumor (12-16). Studies have shown that type I and II rHu-IFNs can site and (/>)decreased toxicity to normal organs such as bone amplify the level of expression of class I and II histocompati- marrow, as well as to those organs that may be involved in bility antigens, as well as some specific tumor antigens found immunoglobulin catabolism. on the surface of human melanoma and adenocarcinoma cell Two studies have recently compared i.p. and i.v. MAb ad populations (see Table 2 and Refs. 15 and 17-27). Previous ministration in animal models for the detection of peritoneal studies have also demonstrated that different species of recom carcinoma. Using MAb HMFG2 and xenografts of the LoVo binant leukocyte interferon (rHu-IFN-aA) can exert different human colon carcinoma cell line, Rowlinson et al. (33) have amounts of antigen augmentation when tested on human tumor observed that i.p. MAb inoculation is better than i.v. for target cell populations. Fig. 1 exemplifies the up-regulation of the ing of peritoneal tumors. Ward et al. (34), using athymic mice tumor associated antigen by rHu-IFN-oA recognized by MAb bearing both s.c. and i.p. human ovarian carcinoma xenografts, B6.2. Other investigators have reported this same heterogeneity reported enhanced localization to ascites tumor cells after i.p. among the different rHu-IFN-a subspecies with respect to MAb inoculation but, in contrast to the previous study, ob eliciting other biological actions (i.e.. antigrowth, natural killer served no advantage of i.p. MAb administration in detection of activity, etc.) (28, 29). More recently, we reported that the IFN- i.p. solid tumor. In one study, therapy of peritoneal carcino- induced changes in cell surface antigen expression that were matosis of human colon cancer xenografts with i.p. 90Y-anti- initially observed with human tumor cell lines could also be carcinoembryonic antigen MAb has demonstrated a significant shown to occur in vivo. In those studies (22), athymic mice decrease in tumor burden 12 days after MAb treatment (35). bearing a human colon xenograft were shown to localize more Hnatowich et al. (36), using i.p. administered 90Y-labeled MAb of a radiolabeled MAb after treatment with rHu-IFN-aA. Other OC-125 for detection of carcinoma in patients with documented investigators (30, 31) have reported that class II histocompati- or suspected ovarian cancer, demonstrated tumontissue ratios bility antigens could also be modulated on human lymphoid of 3:1 to 25:1. The amount of radioactivity retained in the cells, as well as on human tumor xenografts, after the admin peritoneum varied among the patients, suggesting individual istration of the type II rHu-IFN-7. Thus, the data suggest that differences in peritoneal diffusion capabilities which must be the rHu-IFNs can act as potent modulators of cellular antigens taken into account when designing therapeutic protocols. Im- which may be used to enhance the targeting of a conjugated munotherapy i.p. using 13ll-labeled MAb HMFG2 has been MAb to a tumor cell population. reported in one patient with stage III ovarian carcinoma resist In the previous study (22), rHu-IFN-aA significantly in ant to chemotherapy (37). creased I25I-B6.2 binding to (a) human colon tumor extracts Our laboratory has undertaken studies to: (a) determine the and (b) the localization of the radioconjugated MAb to the feasibility of i.p. administration of radiolabeled B72.3 for tumor surface of the colon xenograft. These studies and others (15, targeting (via both gamma scanning and direct analyses of 32); (a) have demonstrated the relationship between the in vitro biopsy specimens); (b) determine the specificity of tumor tar- 821s

Table 2 Summary: Interferon enhancement of tumor antigen expression Â±IFN, No MAb Cell type/antigen(s) Interferon Ref. Colon: CEAÂ° Lymphoblastoid 18

Melanoma associated antigen Â»(Cantell) 19

Breast and colon: TAG-72, CEA. Â«(clone A) 15 M, 90.000

Melanoma. M, 80.000 ree. â€¢¿>â€¢ 20 Ganglioside <.,, â€¢¿

Melanoma ree. -r 21 Cytoplasmic MAA

Melanoma. M, 32,000. 38.000. ree. y 17 46.000. and 50,000

Colon, M, 90,000, in vivo local ree. Â«(clone A) 22 ization

Neuroblastoma. 4-6 different an ree. y 23 tigens

Colon, breast, lung, melanoma, ree. y 24 and EBV-transformed B-cells; Mill antigen

Breast: M, 90,000 ree. a-2b 25

0 B6.2 Melanoma: 96.5 Ag in vivo pa Â«(Cantell) 26 Â£ tient data O Human serous effusions: TAG- ree. a (clone A) ÃŸ(ser)and y 27 U 72, CEA " CEA, carcinoembryonic antigen: MAA. melanoma associated antigen: EBV, Z Epstein-Barr virus; ree., recombinant. O geting by the concomitant i.p. administration of '"I-labeled B72.3 and an isotype matched control I25l-labeled M Ab BL-3 (antiidiotype) IgG; (c) compare tumor localization of i.v. versus i.p. administered MAb by the simultaneous administration of '"I-labeled B72.3 IgG i.v. and "'I-labeled B72.3 IgG i.p.; and (d) define the pharmacokinetics of plasma clearance of both i.p. and i.v. administered radiolabeled MAb B72.3. These studies have been detailed elsewhere (38-40) and are reviewed here. All patients in these studies were part of a preexisting pro + IFN, B6.2 tocol for the surgical resection of metastatic colorectal cancer lesions followed by i.p. administration of therapeutic agents; all patients had confirmed or suspected metastatic peritoneal le sions. Four to 7 days before surgery, all patients were given '"I-labeled B72.3 IgG i.p. via a catheter. tSpggggS., l i if/y Ã•'â€¢¿.'â€¢¿"-- r* -->y~- ^ Previous studies (38, 39) using i.v. administered '" I-labeled B72.3 IgG have shown that differences in administration of between 0.2 and 20 mg of IgG or between 0.8 and 10 mCi of 13II(with a specific activity range of 0.3 to 11.85 mCi/mg) had little or no effect on the radiolocalizaciÃ³n of colon carcinoma lesions as determined by gamma scanning or direct analysis of tumor samples (%ID/kg). Therefore, all patients received be tween 0.76 and 1.2 mg of IgG and between 5.0 and 10.0 mCi 'â€¢"I,withspecific activities of '"I-B72.3 IgG ranging from 6.6 to 11.0 mCi/mg (40). On the day of or prior to surgery, patients were scanned with Fluorescence Intensity a gamma camera; all scan results were interpreted before sur Fig. 1. Fluorescence-activated cell sorter analysis of MAb B6.2 binding to the gery. Gamma scans of 7 of 10 patients showed clearly discern surface of human colon carcinoma cells. Effect of rHu-IFN-aA. The flow cyto- metric analysis was done, using an Ortho Cytofluorograf System 50H, with blue ible concentrations of radiolabeled MAb in various distinct laser excitation of 200 mW at 488 nm. WiDr cells were incubated for 24-36 h in growth medium with or without 850 antiviral units rHu-IFN-nA/ml, harvested, and incubated in culture medium containing 2 ng MAb B6.2/106 cells for 30 min fluoresces red while surface immunofluorescence bound to the M, 90,000 tumor at 4Â°C.The cells were then washed thoroughly with Ca2*-Mg!*-free Dulbecco's antigen fluoresces green. Data from 25,000 cells were stored on an Ortho Model phosphate buffered saline and then treated with fluoresceinated goat anti-mouse 2150 computer system and used to generate each 3-dimensional isometric display IgG (heavy and light chains) (1:30 dilution) for 30 min at 4Â°C.The cells were of DNA content ( Y axis), fluorescence intensity, i.e., cell surface expression of washed, excess antibody was removed, and the cells were resuspended at a the B6.2 reactive M, 90.000 tumor antigen (X axis), and the number of cells (Z concentration of 10' cells/ml and stained with propidium iodide (18 ng/ml) and Ã›.VM).A,WiDr cells stained for DNA content but no MAb B6.2; B, WiDr cells RNase A (2000 units/ml) for 4 h at room temperature. The stained cells were stained for nuclear DNA and B6.2 binding: C, WiDr cells treated with 850 analyzed; under these conditions, propidium iodide bound to nuclear DNA antiviral units rHu-IFN-nA for 24-36 h and stained as in B. 822s

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1990 American Association for Cancer Research. PHARMACOLOGY OF MAB GUIDED TUMOR TARGETING regions of the peritoneum. In all such cases, these lesions were while these results demonstrate the specificity of the B72.3 binding, they do point out that "nonspecific" binding of irrele identified at surgery as tumor and later confirmed as carcinoma via histopathological examination. vant MAb to carcinoma lesions may and does indeed occur at Three of the 10 patients studied were positive for MAb times. localization via gamma scanning (areas confirmed as tumor at Simultaneous i.p. and i.v. Administration of MAb B72.3. Stud surgery) but were negative for tumor via computer-assisted ies were next conducted to determine the relative efficacies of tomographic scanning and X-ray studies. Lesions as small as i.p. versus i.v. administered MAb to localize tumor lesions (40). approximately 1.5 cm in diameter were clearly defined via To achieve this goal, patients were concomitantly given IJ1I- gamma scans. labeled B72.3 i.p. and '"Â¡-labeled B72.3 i.v. Both the i.p. and All specimens removed at surgery were analyzed for cpm/kg i.v. administered MAb preparations in each of four patients of tissue. Specimens were then fixed, embedded, and analyzed were identical as far as mg dose and radiolabeling conditions. for percentage of carcinoma cells present. Table 3 shows the In 35 or 55 carcinoma lesion biopsies obtained, the i.p. admin RI values (based on % ID MAb uptake per kg of tissue) of the istered B72.3 localized at least 2 times better in terms of %ID/ biopsy specimens of tumor and normal tissues from the 10 kg than the i.v. administered MAb. In 7 lesions MAb localiza patients receiving i.p. administered MAb B72.3. An RI of &3 tion was comparable via either route, and in 13 lesions the i.v. was arbitrarily chosen as a "positive" radiolabeled uptake. administered MAb B72.3 localized at least 2 times better than Eighty-three of 112 (74%) of carcinoma lesions showed RI the i.p. administered MAb. For example, as seen for patient values >3. In some patients with a large tumor burden, as much NJ (Table 4), %ID/kg taken up by carcinoma lesions ranged as 40% of the injected dose was found bound to carcinoma. from 11.4 to 45.3 for i.p. administered B72.3 ('"I) versus values Note that of the 29 lesions negative for MAb uptake, 11 were of only 2.8 to 11.3% %ID/kg for the i.v. administered B72.3 from patient MG, the only patient in whom all tumor lesions (I25I). The ratios of uptake of the i.p. administered MAb were were negative for TAG-72 antigen expression. Of the 95 his- from 2.8 to 7.6 times greater for individual lesions than the i.v. tologically confirmed normal tissues biopsied, all but one dem administered MAb. The levels of uptake in the normal tissues onstrated RI values <3 (Table 3). The one biopsy not in this of the i.v. and i.p. administered B72.3 IgG were similar (40). category had an RI of 3.5 and was a histologically normal In an attempt to define the reason(s) for the divergence in spleen; this patient also had the highest level of circulating uptake of i.p. and i.v. administered MAb among different antigen/'"I-B72.3 IgG immune complex as determined by high carcinoma lesions, three pathologists independently examined performance liquid chromatography and radioimmunoassay. these lesions and characterized them as to various properties. The other 94 normal tissue biopsies with RI values <3 were The most striking correlation with differential MAb uptake was from numerous sites, including colon, spleen, ileum, pancreas, whether a given metastasis was a peritoneal implant or "non- lymph node, fallopian tube, liver, ovary, duodenum, and kidney; implant." Metastatic lesions were characterized as (a) perito the vast majority of RI values for normal tissues ranged from neal implants or (b) nonimplant mÃ©tastases,i.e., hematoge- 0.5 to 1.5(40). nously borne mÃ©tastases,lymph node mÃ©tastases,or local re Specificity of MAb B72.3 Radiolocalization. To determine if currences. For those lesions where all three pathologists did the radiolocalization observed with the i.p. administered 'â€¢"!- not arrive at the identical conclusion, the lesion was listed as B72.3 IgG was specific, four patients received concomitant "unclassified." In all 10 nonimplant mÃ©tastasesfrom three infusions (administered i.p.) of '"I-B72.3 IgG and 125I-labeled patients, the ratios (%ID/kg) of uptake of the i.v. injected B72.3 control MAb BL-3 IgG. B72.3 and BL-3 were administered at were at least 2 times that of the i.p. administered MAb, with the same mg dose and time for each patient. There were some ratios ranging up to 38:1. Conversely, in 35 of 40 lesions important observations obtained in these analyses concerning classified as peritoneal implants, i.p. administered B72.3 local "nonspecific" MAb uptake. MAb BL-3 uptake was negative ized at least 2 times better than i.v. administered MAb, with (i.e., RI <3) in 28 carcinoma lesions but showed RI values >3 the ratios obtained for the majority of lesions being greater in 11 others. When the ratios of %ID/kg of these lesions for than 5:1. Five of 40 peritoneal implants bound comparable B72.3 versus BL-3 were analyzed, in none of the 39 lesions was levels of i.p. and i.v. administered B72.3. BL-3 uptake greater than that of B72.3. In 8 lesions the ratios Pharmacokinetics of Plasma Levels after i.p. MAb Adminis were comparable, and in 31 of 39 lesions the B72.3/BL-3 ratios tration. Plasma samples from eight patients studied were ob were >2:1, with ratios of >10:1 in the majority of cases; ratios tained before MAb administration and at various time points of > 100:1, moreover, were observed for many lesions. Thus, post-MAb administration (40). The plasma clearance of the i.v. administered 125I-B72.3IgG and the '"I-BL-3 control IgG were

Table 3 Radiolocalization index valuesfor tissues of patients given i.p. injections similar, with approximately 50% of the injected dose in the of"'l-labeledB72.3Â° plasma at day 2 and approximately 10% of the injected dose in Tumor Normal plasma at day 7 post-MAb administration. In contrast, no more NameNJMHRKMMMGWJEPSMJBJKTotal3-1014350776003329RI>10170018032163SO45RK31210811725]61239599RI3-100000000010!1RI>10000000000000than 30% of the injected dose of i.p. administered B72.3 or BL- 3 IgG appeared in the plasma at any point in time, with peak values being obtained at days 2 to 3. The appearance of '"I-B72.3 IgG in the plasma was noted to be reduced in four of eight patients studied in that '"I-labeled MAb levels in plasma did not rise above 10-12% of injected dose. Pre-MAb administration plasma samples were tested for the B72.3 reactive antigen TAG-72 via RIA as described pre viously (41, 42) and revealed that sera from these four patients lesions%RK3025411205002926RI showed the highest levels of circulating TAG-72 antigen. Several diagnostic and potentially therapeutic applications " Taken from Colcher et al. with permission (40). can be envisioned from these studies. Radiolabeled MAbs such 823s

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1990 American Association for Cancer Research. PHARMACOLOGY OF MAB GUIDED TUMOR TARGETING Table 4 Concomitant administration ofn'l-B72.3 i.p. and '"I-B72.3 i.r. (patient ,\'J): advantage of i.p. route"

ID/kgi.p.44.5140.0439.6239.2711.4145.2727.0827.2329.300.070.520.841.210.991.042.70i.V.5.855.419.198.452.7511.307.547.7610.720.050.490.660.780.470.373.45% ID/kg ratios7.617.395.644.654.164.013.683.482.771.311.071.261.562.092.820.78i.p.131,32.629.329.028.88.433.219.819.921.50.1(1.40.60.90.70.82.0RI*i.V. descriptionCarcinomaOmentumMesentery,Tissue '"I12.211.319.117.65.723.515.716.222.30.11.01.41.61.00.87.2tumor808066SO40856368690000000

colonPeritonealsigmoid 4)Peritonealliver capsule (n = junctionOmentum,gastroesophageal greaterPeritoneal peripancreasOmentum. 2)Diaphragmlesser (n = 3)Peritoneal (n = 4)NormalAdiposespleen, capsule (n =

tissueMesentery, colonPeritoneum,transverse rightPeritoneal 3)Abdominaladhesions (n = scarFalciform ligamentSpleen (n = 3)% *Taken from Colcher et al. with permission (40). *RI was determined by dividing the ''Â¿ID/kgof the tumors by the averaged %ID/kg of all normal biopsies.

as B72.3 may now be considered for use in the localization of area was determined for all animals and humans in this study. suspected colorectal or ovarian carcinoma lesions. Radiolabeled A strong correlation was shown to exist between body surface B72.3 can also be used, along with the serum assay for the area and time to peak percentage of MAb injected dose in the presence of TAG-72 antigen, to monitor efficacy of various plasma after i.p. MAb administration. Mice and rats with body therapies. These studies (40) also demonstrated that carcinoma surface areas of 0.78-4.89 cm2 had time intervals of 2-5 h for was detected by i.p. administered '"I-labeled B72.3 but could peak MAb plasma levels. In contrast, monkeys, with an average not be detected by computer-assisted tomographic scan or other body surface area of 32.1 cm2, reached peak MAb levels at 18- radiographie procedures in 3 of 10 patients studied; lesions as 24 h. Humans, with the largest average body surface area, 212 small as 1.5 cm were detected. Furthermore, efficiency of de cm2, and therefore the largest peritoneal surface area, had the tection should improve when radionuclides, such as 99mTcand longest time interval (24-72 h) between i.p. MAb inoculation '"In, with more favorable imaging characteristics are substi and peak MAb plasma levels. In conclusion, results of Horan tuted for "'I. Hand et a/.5 should be considered by investigators when design Animal Models. In view of the potential advantages of intra- ing preclinical studies using MAbs. peritoneal tumor targeting for diagnosis and/or therapy, com paratively few studies have been undertaken to systematically Studies Concerning the Effect of External Irradiation of Tumor compare the pharmacokinetics of clearance of administered MAb via that route in animal models. Horan Hand et a/.5 have on Localization of Radiolabeled MAb recently completed such a study which is reviewed here. In these One approach to enhance localization of MAb conjugates to studies, mice, rats, and monkeys were given 125I-or '"I-labeled tumor cells may be exposure of tumors to external irradiation B72.3 i.p. and these results were compared to those of patients prior to MAb administration. Alterations in blood flow to the receiving '"I-labeled B72.3 IgG via the same route. tumor may increase accessibility of tumor cells to MAbs. Order To determine which if any animal model is appropriate to et al. (44) suggested that raising the therapeutic ratio for treat study i.p. MAb clearance, data of individual animals were ment of human hepatomas was accomplished by irradiation averaged for each species and compared with the data obtained prior to administration of radiolabeled anti-ferritin polyclonal from human colorectal carcinoma patients inoculated with ra- antibody. Studies in animal models have shown a low level of diolabeled MAb B72.3. Patients who received radiolabeled augmentation of antibody binding after preirradiation of tu MAb B72.3 were those negative by gamma scan. As shown in mors. Using four different syngeneic rat hepatomas and radio- Fig. 2, the peak of MAb in the plasma after i.p. MAb admin labeled anti-ferritin antibody, increases in antibody uptake in istration was approximately 3-4 h for mice and rats and 24 h tumor versus liver after preirradiation of tumors with 1000 cGy for monkeys. In contrast, colorectal carcinoma patients who ranged from 1.1- to 1.5-fold (45). Stickney et al. (46) have also observed a 1.5- to 2-fold enhancement of an '"In-labeled anti- received MAb B72.3 showed the highest average MAb plasma level at 48 h. These results suggest that the rodent may not be p97 MAb to human xenografts pretreated with 1000 cGy of an appropriate model for i.p. MAb studies. external irradiation. The mechanism for these effects was One possible explanation for the vast plasma clearance dif thought to be related to alterations in the tumor vasculature. ferences observed between the 3 animal models and humans Whereas the previous studies were conducted in animal models may be the differences in peritoneal surface area among the using hepatoma (45) or melanoma (46) xenografts and the species. Since it has been suggested that peritoneal surface area clinical trials involved hepatoma patients (44), no studies have is directly proportional to body surface area (43), body surface thus far been reported on the effect of preirradiation on MAb binding in colon carcinomas. 5P. Horan Hand, S. Shrivastav, D. Colcher. P. Snoy, and J. Schlom. Phar These reports led us to study the effect of external irradiation macokinetics of intraperitoneal and intravenous plasma clearance of radiolabeled monoclonal antibodies in rodents, monkeys, and humans, submitted for publica- on MAb targeting of human carcinomas (47); as a model system, we used MAb B72.3 and the LS-174T human colon 824s

Fig. 2. Comparison of i.p. clearance of radiolabeled MAbs in mice, rats, monkeys, and humans. Averages of the percentage of the injected 13'I-MAb B72.3 dose in plasma are shown for 3 athymic and 3 BALB/c mice (â€¢). 3 athymic and 3 Buffalo rats (â€¢).6 monkeys (A), and 3 humans (V). Inset, linear plot of the Xaxis.

0.1 1.0 10.0 100 Time (hours) carcinoma xenograft in athymic mice. LS-174T tumors exposed calization to preirradiated tumors may not be a universal phe- to 300 cGy grew to approximately 93% the size of nonirradiated nomenon. tumors, while those exposed to 600, 900, or 2000 cGy were approximately 41% the size of control tumors. Splitting the Recombinant/Chimeric 900 cGy into three 300-cGy fractions yielded a 2-fold lower tumor volume compared with a single 900-cGy fraction. His- Several chimeric antibodies have been generated using the tochemical evaluation of the carcinomas revealed a decrease in variable region of murine MAb heavy and light chains with the number of mitoses per high power field consistent with human constant regions (see the report of Morrison (48) for early effects of radiation exposure. Using the avidin-biotin review). Recombinant/chimeric MAbs using variable regions complex immunoperoxidase technique, carcinomas were as from murine MAbs against human tumor associated antigens sayed for expression of the TAG-72 antigen. No discernible have recently been reported (49-53). For the most part these variation was observed in the staining intensity among tumors recombinant/chimeric MAbs have been generated using human 7! heavy chain sequences and have been primarily used for in in both the control and radiation treated group; i.e., differences vitro studies of the biological activities of the recombinant/ among tumors within each group were compatible with the known heterogeneous expression of TAG-72. chimeric MAbs, e.g., cell mediated and complement mediated cytotoxicity (54-56). Yokoyama et al. (57) and Steplewski et Exposure of carcinomas to 300 or 900 cGy in a single fraction al. (55) have investigated the in vivo utility of recombinant/ or 900 cGy split in three 300-cGy fractions did not yield a chimeric MAbs to prevent tumor growth in athymic mice consistent or substantial enhanced localization of radiolabeled M Ab B72.3 IgG or F(ab')2 to tumors (Table 5). A 1.5-fold bearing human tumor xenografts, and have shown some utility of the 7! and y4 constructs. Brown et al. (58) have also augmentation of MAb binding to tumors was observed in investigated the in vivo biodistribution of a recombinant/chi preirradiated mice; however, these results were not statistically meric MAb made with a MAb, B6.2 (5), generated against a significant. While our results are different than those reported human mammary tumor associated antigen. with other tumor models, they do not necessarily conflict. Whittle et al. have recently generated a recombinant/chimeric Inherent differences in tumors such as cell type of origin, size, MAb using the variable regions of MAb B72.3 (5) and a human spatial configuration, extent of vascularization, and volume of 74 and Kconstant regions in COS-1 cells (53). We have studied interstitial space may contribute to variability of the effect of the biodistribution of both the recombinant and recombinant/ preirradiation of tumors on antibody binding. Our results sug chimeric B72.3 in a murine tumor xenograft model to deter gest that consistent augmentation of radiolabeled antibody lo- mine the efficacy of the IgG constructs to bind to TAG-72 and to efficiently localize human tumors in situ (59). Table 5 Effect offractionated and single dose irradiation on binding of There are numerous potential advantages to the use of recom radiolabeled MAb B72.3 in athymic mice bearing LS-I74T xenograftsÂ° binant/chimeric immunoglobulins in clinical trials: (a) The dose/gTissueTumor % of injected reduction and/or elimination of the human immune response to the mouse immunoglobulin, since much of the murine im- x 300cGy14.6 cGy12.1 Â±4.3* Â±3.6 Â±2.4 munoglobulin is now substituted with human constant region. Blood 6.5 Â±2.9 7.9 Â±2.2 9.3 Â±3.0 This manipulation may also reduce or eliminate any human Liver 1.1 Â±0.4 1.5 Â±0.4 1.5Â±0.94.8 antiidiotype response. Several studies have demonstrated that SpleenControl10.60.9 Â±0.43 1.7 Â±1.4900 Â±7.8 " Taken from Shrivastav et al. with permission (47). a significant portion of patients who have been given murine 4 Values represent the mean Â±SD of the percentage of injected dose per g of MAbs develop an anti-murine immunoglobulin response (60- tumor and normal tissue for 7-8 mice. 65). This immunological response may be reduced by the use 825s

of fragments of the murine MAb (64), but it should be further 8. Thor, A.. Viglione. M. J.. Muraro, R., Ohuchi, N., Schlom. J., and Gorstein, F. Monoclonal antibody B72.3 reactivity with human endometrium: a study minimized by the use of human monoclonal antibodies. Several of normal and malignant tissues. Int. J. Gynecol. Pathol., 6: 235-247, 1987. groups have used an alternative approach of using the variable 9. Thor, A.. Ohuchi, N.. Szpak. C. A.. Johnston. W. W.. and Schlom. J. The distribution of oncofetal antigen TAG-72 recognized by monoclonal antibody regions of murine MAbs made against tumor associated anti B72.3. Cancer Res.. 46: 3118-3124, 1986. gens and the constant regions of various human IgGs to gen 10. Horan Hand. P., Nuli, M., Colcher, D.. and Schlom. J. Definition of erate recombinant/chimeric MAbs. The recombinant/chimeric antigenic heterogeneity and modulation among human mammary carcinoma cell populations using monoclonal antibodies to tumor-associated antigens. MAbs should retain the specificity of the murine MAb but they Cancer Res., 43: 728-735, 1983. may be less immunogenic in patients since the majority of the Schlom, J.. Colcher, D.. Horan Hand. P., Wunderlich, D., Nuti. M., and IgG molecule contains human sequences. Preliminary studies Teramoto, Y. A. Antigenic heterogeneity, modulation and evolution in breast by LoBuglio et al.6 (66) have demonstrated that while approx- cancer lesions as defined by monoclonal antibodies. In: M. Rich, J. Hager, and P. Furmanski (eds.). Understanding Breast Cancer: Clinical and Labo mately 70% of patients who have been given murine MAb 17- ratory Concepts, pp. 169-213. New York: Marcel Dekker, 1983. 12. Fellous. M., Kamoun, M., Gresser, I., and Bono, R. Enhanced expression of 1A have developed an immune response to the MAb with HLA antigens and ^-microglobulin on interferon-treated human lymphoid approximately 25% of the patients having an antiidiotype re cells. Eur. J. Immunol.. 9:446-449, 1979. sponse, only 1 of 10 patients who have been given a chimeric 13. Giacomini. P., Aguzzi, A., Tecce, R., Fisher, P. B.. and Ferrane, S. Modu form ofthat MAb (human -yU) have generated an anti-17-lA lation by recombinant DNA leukocyte (n) and fibroblast (rf) interferons of the expression and shedding of HLA and tumor associated antigens by idiotype response. (Â¿>)Isotypeswitch variants can now be engi human melanoma cells. J. Immunol., 133: 1649-1655, 1984. 14. Greiner, J. W. Modulation of antigen expression in human tumor cell neered, since cassettes are available of all human constant populations. Cancer Invest., 4: 239-256. 1986. regions. Thus any recombinant/chimeric MAb can now be fitted 15. Greiner. J. W., Horan Hand. P.. Noguchi, P.. Fisher. P. B.. Pestka, S., and with a variety of human constant regions to define optimal Schlom, J. Enhanced expression of surface tumor-associated antigens on human breast and colon tumor cells after recombinant human leukocyte .. pharmacokinetics, effector cell interactions, and complement interferon treatment. Cancer Res.. 44: 3208-3214, 1984. mediated cytotoxicity. (c) Constructs can be engineered for 16. Greiner, J. W., Guadagni, F., Pestka, S., and Schlom, J. Augmentation of alterations in MAb pharmacokinetics. Immunoglobulin domain antigen expression by recombinant human interferon. In: J. A. Roth (ed.), Interferon as Cell Grow th Inhibitors and Antitumor Factors, pp. 17-26. New deletions can be constructed with restriction enzyme technology York: Alan R. Liss, 1985. to prepare smaller recombinant/chimeric constructs. Some of 17. Ziai, M. R., Imberti, L., Longson, A., and Ferrane, S. Differential modulation these may have the advantage of more rapid clearance from the by recombinant immune interferon of the expression and shedding of HLA antigen and melanoma associated antigens by a melanoma cell line resistant body and thus one may achieve higher tumonnormal tissue to the antiproliferative activity of immune interferon. Cancer Res., 45: 5877- MAb binding ratios and, in therapeutic studies, less marrow 5882. 1985. 18. Attallah, A. M.. Needy, C. F., Noguchi, P. D.. and Elisberg, B. L. Enhance toxicity. Smaller constructs should also have the advantage of ment of carcinoembryonic antigen expression by interferon. Int. J. Cancer, better penetration through the tumor mass, (d) Molecular 24:49-52, 1979. alterations in glycosylation sites of a recombinant/chimeric Ig 19. Liao. S. K.. Kwong. P. C.. Khosravi, M.. and Dent, P. B. 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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1990 American Association for Cancer Research. Innovations That Influence the Pharmacology of Monoclonal Antibody Guided Tumor Targeting

Jeffrey Schlom, Patricia Horan Hand, John W. Greiner, et al.

Cancer Res 1990;50:820s-827s.

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