GYNECOLOGIC

ONCOLOGY

38, 244-248 (1990)

Human Anti-murine Antibody Responses in Ovarian Cancer Patients Undergoing Radioimmunotherapy with the Murine Monoclonal Antibody OC-I 25 MICHAEL

G. MUTO, M.D. ,’ NEIL J. FINKLER, M.D., AMIN I.KASSIS, PH.D. ,* EVA MARIE LEPISTO, B.S., AND ROBERT C. KNAPP, M.D.

Divisions of Gynecologic Oncology and *Nuclear Medicine, Departments of Obstetrics and Gynecology and Radiology, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Harvard Medical School, 75 Francis Street, Boston, Massachusettes 02115

Received February 8, 1990

Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-dose intraperitoneal radioimmunotherapy (RIT) with the murine monoclonal antibody OC-125. Sera of patients receiving escalating dosesof OC-125 F(ab’), (lo70 mg) radiolabeled with 18 to 141 mCi of iodine-13’ were assayed for HAMA by a protein A-based radioimmunoassay. Overall, 70% of patients (16/23) developed HAMA within 10 to 46 days (median = 29) postinfusion, with peak values (23 + 6 to 325 2 10 pg/ml) at 32 to 102 days (median = 38). HAMA was undetectable prior to infusion in all casesand persisted up to 76 weeks. Of patients receiving a dose of 123 mCi or less, 80% (16/20) developed HAMA, whereas in the 140-mCi group, none of the three patients had detectable levels. Two patients in the 140-mCi group demonstrated dose-limiting bone marrow toxicity (severe thrombocytopenia and neutropenia). It is concluded that a single intraperitoneal dose of monoclonal antibody leads to a high incidence of HAMA production. The results also suggest that the likelihood of HAMA formation in patients who either had undergone recent chemotherapy or had received the highest dose of the radioimmunoconjugate is reduced. These observations may be of significance in designing multiple-dose therapy trials as HAMA has been demonstrated to decrease antibody-to-tumor binding and may potentially increase renal, hepatic, and hematologic toxicity associated with radioimmunotherapy. Q 1990 Academic PRSS, I~C.

the radioimmunoscintigraphy (RIS) and the radioimmunotherapy (RIT) of cancer patients [l-5]. The development of human anti-murine antibody (HAMA) is common in patients receiving repetitive or single large doses of MoAb [6-101. HAMA has been demonstrated to affect the biodistribution of MoAb by forming antigen-antibody complexes which increase the blood clearance of MoAb and decrease their specific binding to tumor [6,7,11,12]. OC-125 is a murine MoAb raised against the antigenic determinant CA12.5, an ovarian cancer-associated antigen expressed in over 80% of nonmucinous epithelial carcinomas [ 131.We report HAMA responses in 23 ovarian cancer patients undergoing single-dose intraperitoneal RIT with F(ab’), fragments of OC-125 radiolabeled with iodine-13’.

INTRODUCTION Interest

continues

to grow in the potential

diagnostic

and therapeutic applications of murine monoclonal antibodies (MoAb). Radiolabeled MoAb directed against human tumor-associated antigens have been used in both I To whom reprint requests should be addressed at Department of Obstetrics and Gynecology. 244 two-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.

MATERIALS AND METHODS Patients. Between July 1987 and January 1989, 23 patients were enrolled in the radioimmunotherapy trial. Written informed consent was obtained through an approved protocol of the Human Subjects Committee of the Brigham and Women’s Hospital, Boston, Massachusetts. All patients had a confirmed diagnosis of persistent or recurrent epithelial ovarian carcinoma (20 serous, 3 endometrioid), with CA125 antigen levels >35 U/ml. The median age was 54 (range, 31 to 73 years). The majority of the patients presented with advanced, poorly differentiated lesions (Table 1). Exclusion criteria included prior pelvic or abdominal radiation therapy in excess of 3000 cGy; overt thyroid, cardiac, or renal disease; a Karnofsky score ~50; and cytotoxic chemotherapy

TABLE 1 Distribution of Stage and Grade Among Twenty-three RIT Patients Grade Stage

1

1 II III IV

-

2

3

1 (4%) 4 (18%) -

I (4%) 1 (4%) 14 (61%) 2 (9%)

1 month of enrollment. All patients had undergone cytoreductive surgery followed by multiple courses of postoperative chemotherapy, predominantly with cisplatinum-containing regimens. One patient received adjuvant whole-pelvis radiotherapy. In addition, patients with recurrences had undergone aggressive salvage therapy with either intravenous or intraperitoneal administration of a variety of cytotoxic agents. within

Radioimmunoconjugate preparation and RIA administration. OC-125 F(ab’), fragments (Centocor, Malvern,

PA) were radiolabeled with ‘?‘I (NEN DuPont, Billerica, MA) to a specific activity of 2 mCi/mg utilizing a singlevial Iodogen technique [ 141. The radioimmunoconjugate

(RIC) was tested for immunoreactivity by a cell binding assay with OVCAR 433 as described [15]. Pyrogen testing was performed using a chromogenic limulus amoebocyte assay, and sterility was evaluated by a 72 hour incubation in thyoglycolate medium. The content of free iodine was assessed by instant thin-layer chromatography (Gelman Sciences, Ann Arbor, MI). Pyrogen-free RIC with greater than 30% immunoreactivity and less than 10% free iodine was administered to the patient intraperitoneally in all cases by single-lumen catheters as described previously [I]. Serum collection and HAMA assay. Serum was obtained prior to infusion, on a daily basis during the hospital stay, and weekly for at least 6 weeks postinfusion. All samples were stored at -70°C until assayed. Human anti-murine IgG responses were detected by a radioimmunoassay (RIA) described by Mosely [ 161. Briefly, 96-well Remove-A-Well (TC) plates (Dynatech Corp., Chantilly, VA) were coated with protein A (Genzyme, Boston, MA) at a concentration of 10 pug/ml by a 24-hr incubation at 4°C. The plates were washed in 0.1 M phosphate-buffered saline (PBS) containing 10% fetal calf serum and incubated for an additional 24 hr in this buffer. Serum samples, diluted 1: 500 in Tris-HCl buffer, pH 8.0, were added to the precoated plates in a 50-,ul

TABLE 2 Dose of ‘3’I-OC-125 and HAMA Response Patient number

Antibody dose (md

1 2 3 4 5 6 7 8 9 10 11 12 13 14 I5 16 17 18 19 20 21 22 23 * Mean ? SD.

10 10 10 15 15 IS 20 20 30 30 30 40 40 40 50 50 50 60 60 60 70 70 70

‘j’I dose (mCi) 18 20 28 30 20 34 44 42 47 60 54 76 82 87 100 104 105 120 117 123 140 141 140

Follow-up (days) 677 285 51 190 170 536 51 60 41 150 32 56 47 35 60 52 46 53 63 59 54 93 51

Day HAMA first positive 17 10 21 nd 42 18 26 18 28 nd 32 29 40 nd 27 31 37 nd 30 25 nd nd nd

Peak HAMA Wml) 253 ? 27” 319 * 31 234 -t- 25 nd 13 5 4 308 k 34 221 + 25 77 -+ 17 107 + 16 nd 122 * 4 28 k I 23 + 6 nd 29 t 3 124 -+ 12 33 2 6 nd 325 ” 10 112 -c 15 nd nd nd

Interval from prior chemotherapy (months)

5 20 3 1 2 10 5 4 3 2 3 6 14 2 4 22 3 15 11 22 3 5 1

Grade of hematologic toxicity 2 0 0 0 1 0 0 0 2 0 0 2 0 2 2 2 3 2 0 0 1 3 4

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MUTO ET AL.

23). Overall, 70% (16/23) of the patients developed detectable HAMA within 10 to 46 days (median = 29 days) of therapy (Table 2). Peak values ranged from 23 + 6 HAMA detected to 325 ? IO pg/ml and occurred from 32 to 102 days Interval (median = 38 days) following therapy. No patient had Yes (months) No preexisting detectable HAMA prior to infusion. No pa

Human anti-murine antibody responses in ovarian cancer patients undergoing radioimmunotherapy with the murine monoclonal antibody OC-125.

Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-...
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