A new era for radiolabeled antibodies in cancer?

imb516.qxd

10/13/1999 6:52 PM

Page 563

563

A new era for radiolabeled antibodies in cancer? Sally J DeNardo*, Linda A Kroger and Gerald L DeNardo Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3–50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy. Addresses Molecular Cancer Institute, Hematology/Oncology Department, University of California Davis Medical Center, 1508 Alhambra Boulevard, Room 3100, Sacramento, CA 95816, USA *e-mail: [email protected] Correspondence: Sally J DeNardo Current Opinion in Immunology 1999, 11:563–569 0952-7915/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved. Abbreviations CEA carcinoembryonic antigen CLL chronic lymphocytic leukemia CR complete remission HAMA human anti-mouse antibody MoAb monoclonal antibody MTD maximum tolerated dose NHL non-Hodgkin’s lymphoma PBSC peripheral blood stem cell PR partial remission RIT radioimmunotherapy SA streptavidin

using 131I on either the murine or chimeric antibody L6 yielded responses in approximately half of the patients with advanced, chemotherapy-refractory breast cancer who were tested [4]. Similar antitumor responses have been reported in breast cancer using yttrium-90 (90Y) linked to antibodies reactive with epithelial mucin or carcinoembryonic antigen (CEA) [5,6•–8•]. Trials of intraperitoneal RIT therapy as part of combination therapy for ovarian cancer have shown extended remissions and effects on survival [9•,10•]. Here, we present an overview of the current status of RIT and recent results that demonstrate the most useful therapeutic index and/or clinical effects of RIT.

RIT in lymphoma and leukemia In over 500 patients, NHL has proven exquisitely responsive to RIT using a variety of MoAbs and radionuclides. Advantages of RIT in NHL include the accessibility of the malignant lymphocytes to the vascular system, the presence of abundant high-density surface antigens with expression restricted to lymphocytes and the radiosensitivity of NHL. About the time that antiidiotypic immunotherapy was reported, DeNardo et al. [11,12] published the original description of 131I–Lym-1 RIT for patients with NHL and later for patients with chronic lymphocytic leukemia (CLL). Subsequently, others have confirmed the potential of radiolabeled MoAbs for treatment of NHL (Table 1) [13–16]. Press et al. [17] were the first to use a radiolabeled anti-CD20 MoAb, 131I–B1, in association with bone marrow transplantation as a substitute for combination chemotherapy to treat patients with NHL.

Introduction Radioimmunotherapy (RIT) using systemically administered monoclonal antibodies (MoAbs) linked to radionuclides is a promising approach for treating metastatic cancer. RIT can be regarded as ‘smart’ radiotherapy because of specific targeting of malignant lesions, known or occult. The underlying concept of RIT has been extensively reviewed [1–3]. Because of selective concentration of the MoAb — and thus of the radioisotope — in tumor tissue, this modality can deliver substantial doses of radiation to the tumors while minimizing exposure of normal tissue. In addition, RIT is able to target multiple metastases throughout the body in a single treatment (Figure 1). Excellent results have been reported using RIT in advanced hematologic malignancies. Single or multiple non-myeloablative doses or highdose RIT with bone marrow transplantation have produced remarkable results in advanced-stage non-Hodgkin’s lymphoma (NHL) patients whose disease had recurred after standard treatment. Long-term complete remission (CR) following high-dose RIT has been common. Success in solid tumors has been more limited. However, in several cancers useful progress has occurred. Clinical trials

Three commercially sponsored RIT products are in pivotal trials for treating NHL and additional agents are in monitored trials (Table 1). NHL antigenic targets for RIT have included normal B cell antigens (CD20 and CD22) and a subunit of HLA-DR10. CD20 is a 32 kDa nonglycosylated phosphoprotein present on B cells but absent on stem cells and antigen-presenting cells. Anti-CD20 MoAbs react with >95% of B cells and >90% of B cell NHL [13,16,17]. Y2B8 (IDEC Pharmaceuticals Corporation, San Diego), the mouse MoAb parent of C2B8 (Rituxan, IDEC Pharmaceuticals Corporation, San Diego), can be radiolabeled with 90Y using MXDTPA (1,4-methyl-benzyl isothiocyanate diethylenetriamine pentaacetic acid) and is specific for the CD20 antigen. A phase I/II dose escalation trial of 90Y–Y2B8 in patients with recurrent B cell NHL has shown promising results [14]. A total of 51 patients with relapsed low- or intermediate-grade NHL were treated in an outpatient setting, with a 67% overall response rate following a single RIT dose (82% in low-grade NHL). Transient myelosuppression was the primary toxicity. The incidence of human anti-mouse antibody (HAMA) was 2%. A multicenter trial is currently underway to determine whether 90Y–Y2B8 is better than C2B8 alone.

imb516.qxd

10/13/1999 6:52 PM

564

Page 564

Cancer

Table 1 Radioimmunotherapy clinical trials. Disease

Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Lymphoma Leukemia Leukemia Breast Ca Breast Ca Breast Ca Breast Ca Breast Ca Breast Ca Renal Ca Ovarian Ca Ovarian Ca Lymphoma MTC/SCLC

Radiopharmaceutical

90Y–2B8 131I–Anti-B1 131I–Anti-B1 131I–Anti-B1 131I–Anti-B1 131I–Anti-B1/BMT 131I–Anti-B1/BMT 90Y–hLL2 131I–Lym-1

(low dose) (MTD) 90Y–HuM195 213Bi–HuM195 131I–ChL6 90Y–mBrE-3 90Y–mBrE-3 90Y–hBrE-3/PBSC 90Y–cT84.66/PBSC 90Y–m170/PBSC 131I–cG250 177Lu–CC49 90Y–HMFG1 C2B8–SA, 90Y–B anti-CEA–anti-DTPA 131I–hapten 131I–Lym-1

Phase

I/II I/II II II III I/II II I I/II I/II I I I I I I I I I I I/II I I

Antigen

CD20 CD20 CD20 CD20 CD20 CD20 CD20 CD22 HLA-DR10 HLA-DR10 CD33 CD33 L6 MUC-1 MUC-1 MUC-1 CEA MUC-1 MN TAG-72 MUC-1 CD20 CEA

Responses CR

PR*

13 out of 51 20 out of 53 14 out of 45 17 out of 32‡ 10 out of 60 16 out of 19 16 out of 21 See text 3 out of 30 7 out of 21

21 out of 51 22 out of 53 13 out of 45 7 out of 32‡ 29 out of 60 2 out of 19 2 out of 21 See text 14 out of 30 4 out of 21

4 out of 10 1 out of 6 4 out of 8 2 out of 9 1 out of 4 3 out of 27 See text 2 out of 7

See text 2 out of 7 3 out of 36

Reference Minor†

8 out of 12 13 out of 18 2 out of 10 1 out of 6 2 out of 9 2 out of 6 2 out of 4 2 out of 8 1 out of 27

23 out of 36

[14] [13] [49] [19••] [50] [17] [16] [20] [21] [22•] [26•] [27••] [4] [5] [51] [6•] [7•] [8•] [42•] [9•] [10•] [45••] [46••]

*PR denotes a decrease in the sum of the products of all tumor dimensions by at least 50% or all tumor volumes by at least 70%. † Minor response denotes 30–50% reduction in tumor volume, 50–70% reduction in the sum of the products of all tumor dimensions,

mixed response or stable disease. ‡ Of the 32 patients, 8 are not evaluable to date. B, biotin; Ca, cancer; MTC, medullary thyroid cancer; SCLC, small-cell lung cancer.

Anti-B1 (Bexxar®, Coulter Pharmaceutical Incorporated, Palo Alto), a mouse MoAb directed against a different epitope of the CD20 B cell antigen than Y2Β8, is in the final stages of clinical study in NHL. There have been a number of phase I/II trials utilizing 131I–Anti-B1 in the treatment of NHL [18]. A study of particular note is in progress in previously untreated patients with stage 3 or 4 follicular NHL [19••]. Preliminary results showed an overall response rate of 100%. Patients had reversible myelosupression that did not require transfusions or colony-stimulating factor. The overall experience in 166 patients with low-grade NHL or transformed low-grade NHL treated with non-myeloablative doses of 131I–Anti-B1 showed that a single RIT dose produced a 78% response rate and a CR rate of 46% [18].

Incorporated, Morris Plains, New Jersey), has shown high radiation-dose ratios in tumors compared with normal tissues in patients with relapsed/refractory NHL [20]. Two trials — non-myeloablative, or myeloablative with peripheral blood stem cell (PBSC) support — of escalating doses of 90Y–hLL2 are ongoing. Of patients that failed prior high-dose chemotherapy, two out of three had responses lasting up to 12 months. Myeloablative doses of 90Y–hLL2 followed by PBSC support achieved responses in three out of four patients.

Press et al. [16,17] have demonstrated that a single, large treatment dose of 131I–Anti-B1 with bone marrow support was remarkably effective for NHL. To date, 25 out of 29 patients have responded to high-dose treatment with 131I–Anti-B1, followed by bone marrow transplantation [16]. The maximum tolerated dose (MTD) was determined to be 2700 rads to the lung, the dose-limiting organ, given as one dose [16]. Humanized 90Y–LL2 (90Y–hLL2), a rapidly internalizing anti-CD22 MoAb (Lymphocide TM, Immunomedics

Lym-1, an IgG2a mouse MoAb with high affinity against a discontinuous epitope on the β subunit of the HLA-DR10 surface membrane antigen of malignant B cells, can be radiolabeled with 131I and this is currently in a multicenter phase III trial. Since Lym-1 antigen is highly expressed on the surface of malignant human B cells but less so (or not at all) on normal lymphocytes, only 5 mg of unlabeled MoAb is sufficient for optimal tumor targeting. More than 80% of B cell NHL patients and 40% of B cell CLL patients have malignancies reactive with Lym-1. Thirty patients (25 NHL and 5 CLL) with Ann Arbor or Rai stage 3 or 4 Bcell malignancies that had progressed despite standard treatment entered a low-dose, fractionated treatment trial to assess 131I–Lym-1 toxicity and efficacy [21]. Despite 18 patients entering the trial with a Karnofsky performance

imb516.qxd

10/13/1999 6:52 PM

Page 565

A new era for radiolabeled antibodies in cancer? DeNardo, Kroger and DeNardo

565

Figure 2

Figure 1

A

P Current Opinion in Immunology

γ-camera image of the anterior pelvis of a patient with B cell lymphoma. The image was obtained three days after administration of 111In–Lym-1 in order to derive pharmacokinetic data that can be used to calculate dosimetry for therapy with 90Y–Lym-1. Excellent uptake in all known areas of lymphoma is demonstrated in the upper- and mid-abdomen and right iliac lymph nodes (arrows). Radioactivity in the bladder and liver demonstrates 111In–Lym-1 metabolism and 111In metabolite excretion [52]. White is the most intense radiation, followed by red, yellow and green. Blue/black indicates no radiation.

status of less than 60, the overall response rate was 57% (17 out of 30 patients); 13 out of 25 (52%) NHL patients and 4 out of 5 (80%) CLL patients responded. A trial to define the MTD for the first two, of a maximum of four, doses of 131I–Lym-1, given 4 weeks apart, revealed that the nonmyeloablative MTD was 100 mCi/m2; all three patients at this dose level had CRs [22•]. Eleven out of twenty-one patients (52%) responded to 131I–Lym-1 with at least a partial remission (PR) after the first 131I–Lym-1 treatment dose. Fourteen patients received two or more treatment doses and ten (71%) had remissions. HAMA occurred in one third of the patients but interrupted treatment in less than 10%. In these trials, patients that responded to treatment had significantly increased survival even when a multivariate analysis, that included baseline risk factors, was performed [23].

RIT advances for multimodality therapy of leukemia HuM195, a humanized MoAb reactive with the cell surface antigen CD33, specifically targets myeloid leukemia cells [24]. 131I–anti-CD33 conjugates can eliminate large leukemic burdens in patients and have been combined safely with busulfan and cyclophosphamide in 30 patients to eliminate disease before bone marrow transplantation [25]. 90Y–HuM195m is currently under study [26•]. Twelve patients with acute myelogenous leukemia received 0.1–0.3 mCi/kg of 90Y–HuM195 as a singe therapy dose and 111I–HuM195 for biodistribution/dosimetry studies. Non-hematologic toxicity was limited to transient liverfunction abnormalities. At the highest dose level all three

Current Opinion in Immunology

γ-camera image of a patient with metastatic breast cancer. Anterior (A) and posterior (P) aspects of the patient are indicated. The image was obtained three days after RIT with 111In/90Y–DOTA-peptide–ChL6 [34]. DOTA-peptide–ChL6 is a novel immunoconjugate with a catabolizable peptide linker. This three-dimensional, cross-sectional chest image was obtained by SPECT (single photon emission computerized tomography) and demonstrates uptake in metastatic disease in the right anterior chest wall, mediastinal lymph nodes and lung (arrows). No uptake is seen in normal tissues. The high therapeutic index for radiation dose in the tumor (compared with normal tissue) is evident. White is the most intense radiation, followed by red, yellow and green. Blue/black indicates no radiation.

patients had bone marrow biopsies showing no evidence of residual leukemia two weeks after treatment, thereby suggesting that 90Y–HuM195 will be useful as part of a pre-transplant regimen for ablation of the leukemia.

Ground-breaking work using α particles for RIT To increase the antileukemic effect of HuM195, 213Bi was conjugated to it. 213Bi emits an 8 MeV α particle and has a half-life of 46 minutes. Eighteen patients with relapsed/refractory acute myelogeneous leukemia or chronic myelomonocytic leukemia were treated with 213Bi–HuM195 [27 ••]. No acute toxicity has been observed. Delayed non-hematologic toxicity has been limited to transient, low-grade liver function abnormalities. The calculated absorbed dose ratios (comparing organs with leukemic infiltration to the whole body) were 1000–10,000-times greater than those for β-emitting nuclides such as 131I or 90Y [28••]. Of the 12 evaluable patients, 10 had reductions in peripheral blood leukemia cells and 13 of the 18 patients had decreases in the percentage of bone marrow blasts. This is the first study to show that targeted α-particle therapy is feasible in patients and provides a rationale for a further study. Recent preclinical studies in a mouse/human colon cancer model have also shown suprisingly effective results from 213Bi–MoAb RIT [29•].

Breast cancer RIT has been less effective for solid tumors, in part, because they are less radiosensitive. However, radiosensitivity of

imb516.qxd

10/13/1999 6:52 PM

566

Page 566

Cancer

breast cancer has been demonstrated in patients with earlystage disease: conservative surgery followed by external-beam radiation therapy to microscopic residual disease in the breast produces the same local disease-free status and overall survival rates for 8–10 years as does modified radical mastectomy [30–33]. To deliver therapy to widespread tumors at levels achievable by RIT, the doses of external-beam radiation therapy that would be required for the entire body are too toxic. The therapeutic index of RIT now allows between 3- and 50-times the dose of radiation to be delivered to tumor throughout the body, compared with the highest dose in normal tissue (Figure 2) [34]. RIT trials specifically for breast cancer therapy have shown 30–60% clinically relevant (though transient) responses in heavily treated patients. The highest dose in normal organs varies between liver, lung and kidney — depending on the antigen target, the antibody or antibody fragment, the radionuclide and the method of conjugation. RIT agents in current trials for breast cancer frequently deliver 2000–4000 rads per cycle of therapy to metastases when PBSCs are given to support the marrow. Dosimetry studies suggest that 5-times these doses can be safely delivered using the normal tissue tolerance levels that were demonstrated by Press et al. [16,17]. Although single-modality therapy is not likely to be effective in producing extended CRs in metastatic cancer, combined modality therapy with RIT promises to be very effective in breast cancer. Preclinical studies with RIT and Taxol combinations have been reported to induce cures of aggressive, p53-mutant, human breast-cancer models [35•].

Ovarian cancer Like several other adenocarcinomas, the prognosis for ovarian cancer patients is poor. Five-year survival rates for patients who have responded well to the standard treatments, which consists of cytoreductive surgery and chemotherapy, are only 20–40%. 90Y-labeled murine IgG1 MoAb HMFG1 (Theragyn®, Antisoma PLC, London, UK) reacts with an epithelial mucin, a product of the MUC-1 gene, that is expressed at high levels in an abnormally glycosylated form on the cell surface of over 90% of ovarian tumors. Twenty-five patients with epithelial ovarian cancer, stages Ic–IV, received adjuvant intraperitoneal RIT following completion of conventional chemotherapy (i.e. on achieving CR, they received one 25 mg dose of 90Y–HMG1 at 18 mCi/m2) [10•]. A five-year post-therapy analysis examined the long-term survival of patients who received intraperitoneal RIT with 90Y-labeled MoAb [36]. Matching controls were selected on the basis of the stage, the histological grade and type of disease and the age of patients at diagnosis. Kaplan-Meier survival plots were subjected to statistical analysis: survival at five years was 80% for RIT patients and 55% for matched controls (probability = 0.003). The Cox model estimates for long-term (10 year) survival were 70% for patients who received RIT, compared with 32% for those that did not (probability = 0.003). This study shows a likely survival benefit for patients with ovarian cancer who receive intraperitoneal RIT in the adjuvant setting. It may be noteworthy that all patients developed HAMA.

In order to evaluate this therapy in a large multicenter setting, a phase III trial was opened for 300 patients randomized equally between the two treatment-groups. The study is designed to demonstrate a 40% further reduction in mortality at two years for a group receiving standard therapy and intraperitoneal 90Y–HMG1, when compared with the control group of chemotherapy/surgery alone.

Combined agents for synergy in ovarian cancer therapy The anti-TAG-72 antibody, CC49, was radiolabeled with 177Lu (a radiometal with β emissions similar to 131I) and given via intraperitoneal administration as a single agent or with human recombinant interferon-α (subcutaneous) with or without paclitaxel (Taxol) [9•]. Eligible patients had TAG-72-expressing tumor limited to the abdominal cavity after surgery/chemotherapy. Radiation dose ratios of 58–139:1 (comparing tumor : bone-marrow) were obtained. Three patients (out of 27) with small-volume disease have remained without evidence of relapse for 3–5 years. Thus far, intraperitoneal RIT with 177Lu–CC49 alone or with adjuvant (interferon) with or without Taxol has shown antitumor efficacy and extended relapse-free survival in patients who have failed standard therapy (Table 1) [9•].

Progress in treating various cancers using RIT Radiolabeled anti-CEA MoAbs have shown excellent targeting in patients with CEA-producing cancers, such as colorectal, pancreatic, ovarian, breast and medullary thyroid cancers [37–40]. Currently, high-dose myeloablative RIT utilizing a humanized 90Y–MN-14 anti-CEA MoAb (90Y–hMN-14 or CEA-CideTM, Immunomedics Incorporated, Morris Plains, New Jersey) is under study in combination with chemotherapy and followed by PBSC support for treatment of relapsed/refractory CEA-producing cancers (M Juweid, personal communication). Doxorubicin (60 mg/m2) is administered 24 hours after RIT and the doxorubicin is followed by PBSCs [41••]. Thus far, nine patients have been treated with 20–40 mCi/m2 of 90Y–hMN-14. Tolerance of this combination therapy and early evidence of antitumor effects have been encouraging. Chimeric G250 (cG250) targets G250 (a homologue of the MN antigen), a transmembrane phosphoprotein expressed on most renal cell carcinoma (RCC). Excellent uptake of 131I–cG250 in metastatic RCC in patients has been demonstrated and 25% of patients treated at the MTD showed a response [42•].

Engineered antibody systems Experience with conventional RIT has suggested that higher doses of radioactivity are associated with a better response rate. However, the doses of radiation required to achieve the highest response rates have required bone marrow or PBSC support [6•–8•,16]. Pretargeting RIT represents an alternative to conventional RIT that may enable delivery of higher doses of radiation without concomitant myelosuppression

imb516.qxd

10/13/1999 6:52 PM

Page 567

A new era for radiolabeled antibodies in cancer? DeNardo, Kroger and DeNardo

radioisotope (bound to biotin) to the tumor. Because biotin is a small molecule, it localizes quickly to the antibodyreceptor on the tumor and minimizes exposure of non-target-organs to radiation [44••].

Figure 3 (a)

(d)

SA SA

Seven patients with relapsed low- or intermediate-grade NHL have received an anti-CD20 antibody delivered by the Pretarget® method (50–109 mCi of 90Y) [45••]. Doselimiting myelosuppression was not observed, even in patients who had previously been treated with high-dose chemotherapy and bone marrow transplantation. Dosimetry estimates indicated that, with the Pretarget® method, the ratios of radiation doses in the tumor (compared with the whole body) were 2–3-times higher than those achieved with anti-CD20 antibodies in conventional RIT. Two patients achieved a CR and two achieved a PR (H Breitz, personal communication). These preliminary results are encouraging and warrant further dose-escalation to determine the MTD and the response at the MTD.

SA

SA

Tumor cell

Tumor cell (e)

(b) Chase

∗

∗

SA Chase

∗ (f)

SA ∗

(c) Bi∗

567

Bi∗

Bi∗ SA–Bi∗

SA–Bi∗ Current Opinion in Immunology

Examples of pretargeting strategies currently in clinical trials. (a) SAconjugated antibody is administered and localizes at the tumor site. (b) A ‘chase’ reagent is administered to completely clear any unbound antibody from the circulation. (c) A small moiety (here biotin [Bi]) is radiolabeled (∗) and is designed to bind the localized antibody (here via SA). Because of its small size, any radioactive molecule that is not tumor-bound is quickly excreted by the kidney. (d) In another strategy, bispecific antibodies bind the tumor via one of their specific arms. The other specificity is for a small hapten, which can (e) be radiolabeled; like biotin, any excess hapten is quickly excreted. (f) Bound hapten can cross-link the bispecific antibody bound to the tumor.

(Figure 3) [43••]. One approach encompasses a three-step delivery system (Pretarget®, NeoRx Corporation, Seattle) in which the radioactivity is injected separately from the antibody, thereby minimizing exposure of the marrow stem cells to circulating radiation. In the first step, an antibody conjugated to streptavidin (SA) is injected and allowed to accumulate at the tumor sites. Secondly, a synthetic clearing agent that binds circulating conjugates of antibody–SA is injected and clears the conjugate from the circulation via the liver. The final Pretarget® step exploits the ultra-high-affinity interaction between biotin and SA to deliver a

A different pretargeting approach, referred to as the affinity enhancement system (AES), uses bispecific antibodies and radiolabeled bivalent haptens that bind co-operatively to target cells in vivo [46••]. Experimental and clinical data demonstrate that AES can deliver large radiation doses to tumor cells because of high ratios in tumors, compared with normal tissues, and because of long residence time in tumors. Patients received the bispecific antibody and, four days later, 131I-labeled bivalent hapten in the context of a dose-escalation study spanning 40–200 mCi. In 23 patients with recurrent or metastatic medullary thyroid carcinoma, 5 had minor responses, 5 had stable disease and 5 had a significant decrease in bone pain. In 13 small-cell lung cancers, 3 PRs and one stable disease were observed. Dosimetry demonstrated an excellent therapeutic index; dose-limiting toxicity was hematological and easily manageable.

Conclusions Immunotherapy and RIT have ushered in a new era in the treatment of cancer. The therapeutic index that can presently be achieved by RIT provides a tool for new combined-modality therapy for many cancers. As the field of antibody engineering comes of age, formerly theoretical questions regarding optimized pretargeting molecules and the most effective linkages for radionuclides take on practical relevance [47,48]. The ability to generate new constructs, such as bivalent antibodies or fusion proteins incorporating two disparate functional proteins, opens up exciting opportunities for new therapy. The role of multifunctional antibody-derived molecules is likely to increase in importance, not only as a means of targeting radionuclides but also as an effective technique for eliciting other tumoricidal effects.

Acknowledgements Colleagues from industry and other institutions have generously provided current information even occasionally when not yet in detailed publication.

imb516.qxd

10/13/1999 6:52 PM

568

Page 568

Cancer

monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res 1996, 2:457-470.

The authors’ work was supported in part by grant number PHS CA-47829 from the National Cancer Institute, Bethesda.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest •• of outstanding interest 1.

Zuckier LS, DeNardo GL: Trials and tribulations: oncological antibody imaging comes to the fore. Semin Nucl Med 1997, 27:10-29.

2.

DeNardo GL, O’Donnell RT, Oldham RK, DeNardo SJ: A revolution in the treatment of non-Hodgkin’s lymphoma. Cancer Biother Radiopharm 1998, 13:213-223.

3.

Farah RA, Clinchy B, Herrera L, Vitetta ES: The development of monoclonal antibodies for the therapy of cancer. Crit Rev Eukaryotic Gene Expr 1998, 8:321-356.

4.

5.

DeNardo SJ, O’Grady LF, Richman CM, Goldstein DS, O’Donnell RT, DeNardo DA, Kroger LA, Lamborn KR, Hellstrom KE, Hellstrom I, DeNardo GL: Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody. Anticancer Res 1997, 17:1745-1752. DeNardo SJ, Kramer EL, O’Donnell RT, Richman CM, Salako QA, Shen S, Noz M, Glenn SD, Ceriani RL, DeNardo GL: Radioimmunotherapy for breast cancer using indium-111/yttrium90 BrE-3: results of a phase I clinical trial. J Nucl Med 1997, 38:1180-1185.

6. •

Cagnoni PJ, Ceriani RL, Cole WC, Johnson T, Quaife R, Nieto Y, Matthes S, Shpall EJ, Bearman SI, Taffs S et al.: Phase I study of high-dose radioimmunotherapy with 90-Y-hu-BrE-3 followed by autologous stem cell support (ASCS) in patients with metastatic breast cancer [abstract]. Cancer Biother Radiopharm 1998, 13:328. References [6•–8•] describe current effective studies of RIT in breast cancer, with PBSC support. 7. •

Wong JYC, Somlo G, Odom-Maryon T, Williams LE, Liu AY, Yamauchi DM, Wu AM, Shively JE, Forman S, Doroshow J, Raubitschek AA: Initial results of a phase I trial evaluating 90yttrium (90Y)-chimeric T84.66 (cT84.66) anti-CEA antibody and autologous stem cell support in CEA-producing metastatic breast cancer [abstract]. Cancer Biother Radiopharm 1998, 13:314. See annotation [6•].

8. •

Richman CM, DeNardo SJ, O’Donnell RT, Goldstein DS, Shen S, Kukis DL, Kroger LA, Yuan A, Boniface GR, Griffith IJ, DeNardo GL: Dosimetry-based therapy in metastatic breast cancer patients using 90Y Mab 170H.82 with autologous stem cell support and cyclosporin A. Clin Cancer Res 1999, in press. See annotation [6•].

9. •

Meredith RF, Alvarez R, Khazaeli MB, LoBuglio A: Intraperitoneal radioimmunotherapy for refractory epithelial ovarian cancer with 177Lu-CC49. Minerva Biotechnologica 1998, 10:100-107. This paper describes the first RIT/Taxol combination in patients with ovarian cancer. 10. Nicholson S, Gooden CSR, Hird V, Maraveyas A, Mason P, Lambert HE, • Meares CF, Epenetos AA: Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis. Oncology Rep 1998, 5:223-226. This article demonstrates statistically significant, enhanced survival that is associated with the use of RIT as an adjuvant in ovarian cancer therapy. 11. DeNardo SJ, DeNardo GL, O’Grady LF, Macey DJ, Mills SL, Epstein AL, Peng J-S, McGahan JP: Treatment of a patient with B cell lymphoma by I-131 Lym-1 monoclonal antibodies. Int J Biol Markers 1987, 2:49-53. 12. DeNardo SJ, DeNardo GL, O’Grady LF, Hu E, Sytsma VM, Mills SL, Levy NB, Macey DJ, Miller CH, Epstein AL: Treatment of B cell malignancies with I-131 Lym-1 monoclonal antibodies. Int J Cancer 1988, 3(suppl 3):96-101. 13. Kaminski MS, Zasadny KR, Francis IR, Fenner MC, Ross CW, Milik AW, Estes J, Tuck M, Regan D, Fisher S et al.: Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996, 14:1974-1981. 14. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles T-M, Grillo-Lopez AJ, Chinn P, Varns C, Ning S-C et al.: Yttrium-90-labeled anti-CD20

15. White CA, Halpern SE, Parker BA, Miller RA, Hupf HB, Shawler DL, Collins HA, Royston I: Radioimmunotherapy of relapsed B-cell lymphoma with yttrium 90 anti-idiotype monoclonal antibodies. Blood 1996, 87:3640-3649. 16. Press OW, Eary JF, Appelbaum FR, Martin PJ, Nelp WB, Glenn S, Fisher DR, Porter B, Matthews DC, Gooley T, Bernstein ID: Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 1995, 346:336-340. 17.

Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko GM, Fisher LD, Porter B et al.: Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 1993, 329:1219-1224.

18. Vose J, Saleh M, Lister A, Rohatiner A, Knox S, Radford J, Zelenetz AD, Stagg R, Tidmarsh G, Wahl R, Kaminiski MS: Iodine-131 Anti-B1 antibody for non-Hodgkin’s lymphoma (NHL): overall clinical trial experience [abstract]. Proc Am Soc Clin Oncol 1998, 17:10. 19. Kaminski MS, Gribbin T, Estes J, Ross CW, Regan D, Zasadny K, •• Tamminen J, Kison P, Tuck M, Fisher S et al.: I-131 anti-B1 antibody for previously untreated follicular lymphoma (FL): clinical and molecular remissions [abstract]. Proc Am Soc Clin Oncol 1998, 17:2. The authors report the first use of RIT for previously untreated lymphoma and demonstrate uniquely high response rates. 20. Juweid ME, Stadtmauer E, Sharkey RM, Hajjar G, Suleiman S, Luger S, Swayne LC, Alavi A, Goldenberg DM: Pharmacokinetics, dosimetry and initial therapeutic results with 131I- and 111In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody (MAb) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). Clin Cancer Res 1999, in press. 21. DeNardo GL, DeNardo SJ, Lamborn KR, Goldstein DS, Levy NB, Lewis JP, O’Grady LF, Raventos A, Kroger LA, Macey DJ et al.: Low-dose fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody. Cancer Biother Radiopharm 1998, 13:239-254. 22. DeNardo GL, DeNardo SJ, Goldstein DS, Kroger LA, Lamborn KR, • Levy NB, McGahan JP, Salako QA, Shen S, Lewis JP: Maximum tolerated dose, toxicity, and efficacy of 131I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma. J Clin Oncol 1998, 16:3246-3256. The authors demonstrate that >50% of heavily pretreated lymphoma patients showed at least a PR after the first of several RIT doses; all three patients given the MTD had CRs with non-myeloablative doses. 23. DeNardo GL, Lamborn KR, Goldstein DS, Kroger LA, DeNardo SJ: Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Cancer 1997, 80(suppl 12):2706-2711. 24. Feldman E, Kalaycio M, Schulman P, Frankel S, Weiner G, Schwatzberg L, Velez-Garcia E, Jurcic J, Scheinberg D, Wedel N: Humanized monoclonal anti-CD33 antibody HuM195 in the treatment of relapsed/refractory acute myelogenous leukemia (AML): preliminary report of a phase II study [abstract]. Proc Am Soc Clin Oncol 1999, 18:4. 25. Jurcic JG, Caron PC, Nikula TK, Papadopoulos EB, Finn RD, Gansow OA, Miller WHJ, Geerlings MW, Warrell RPJ, Larson SM, Scheinberg DA: Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. Cancer Res 1995, 55(suppl 23):5908-5910. 26. Jurcic JG, Divgi CR, McDevitt MR, Ma D, Sgouros G, Finn RD, • Larson SM, Scheinberg DA: Potential for myeloablation with yttrium-90-labeled HuM195 (anti-CD33): a phase I trial in advanced myeloid leukemias [abstract]. Blood 1998, 92:613. This paper suggests that 90Y–HuM195 will be useful as part of a pretransplant regimen for the ablation of leukemia. 27. ••

Jurcic JG, McDevitt MR, Sgouros G, Ballangrud A, Finn RD, Ma D, Hamacher K, Geerlings MW, Humm JL, Brechbiel MW et al.: Phase I trial of targeted alpha-particle therapy for myeloid leukemias with bismuth-213-HuM195 (anti-CD33) [abstract]. Proc Am Soc Clin Oncol 1999, 18:7. References [27••,28••] report the first studies to show that targeted α-particle therapy is feasible in humans and provide targeting ratios (comparing tumors with whole-body doses) that are 1000–10,000-times those calculated for β-emitting nuclides in leukemia patients.

imb516.qxd

10/13/1999 6:52 PM

Page 569

A new era for radiolabeled antibodies in cancer? DeNardo, Kroger and DeNardo

28. Sgouros G, Ballangrud AM, Humm JL, Jurcic JG, McDevitt MR, Erdi YE, •• Mehta BM, Finn RD, Geerlings MW, Larson SM, Scheinberg DA: Pharmacokinetics and dosimetry of an alpha-particle emitter labeled antibody: 213Bi-HuM195 (anti-CD33) in patients with leukemia. J Nucl Med 1999, in press. See annotation [27••]. 29. Behr TM, Behe M, Stabin MG, Wehrmann E, Apostolidis C, Molinet R, • Strutz F, Fayyazi A, Wieland E, Gratz S et al.: High-linear energy transfer (LET) α versus low-LET β emitted in radioimmunotherapy of solid tumors: therapeutics efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO10-1A Fab’ fragments in a human colonic cancer model. Cancer Res 1999, 59:2635-2643. This preclinical study demonstrates surprisingly effective therapy with α-particle-targeted RIT. 30. Fisher B, Redmond C, Poisson R, Margolese R, Wolmark N, Wickerham L, Fisher E, Deutsch M, Caplan R, Pilch Y et al.: Eightyear results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989, 320:822-828. 31. Lichter AS, Lippman ME, Danforth DNJ, D’Angelo T, Steinberg SM, DeMoss E, MacDonald HD, Reichert CM, Merino M, Swain SM et al.: Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 1992, 10:976-983. 32. Sarrazin D, Le MG, Arriagada R, Contesso G, Fontaine F, Spielmann M, Rochard F, LeChevalier T, Lacour J: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989, 14:177-184. 33. van Dongen JA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthuis G, van der Schueren E, Sylvester R, Winter J, van Zijl K: Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. Monogr Natl Cancer Inst 1992, 11:15-18. 34. DeNardo SJ, Richman CM, Goldstein DS, Shen S, Salako QA, Kukis DL, Meares CF, Yuan A, Welborn JL, DeNardo GL: Yttrium-90/indium111-DOTA-peptide-chimeric L6: pharmacokinetics, dosimetry and initial results in patients with incurable breast cancer. Anticancer Res 1997, 17:1735-1744. 35. DeNardo SJ, Richman CM, Kukis DL, Shen S, Lamborn KR, Miers LA, • Kroger LA, Perez EA, DeNardo GL: Synergistic therapy of breast cancer with Y-90-chimeric L6 and paclitaxel in the xenografted mouse model: development of a clinical protocol. Anticancer Res 1998, 18:4011-4018. The authors describe the synergistic effect of Taxol and RIT in preclinical studies and the approach that applies the time/dose information to clinical protocol development. 36. Maraveyas A, Snook D, Hird V, Kosmas C, Meares CF, Lambert HE, Epenetos AA: Pharmacokinetics and toxicity of an yttrium-90CITC-DTPA-HMFG1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer 1994, 73:1067-1075. 37.

Goldenberg DM, Kim EE, DeLand FH, Benett S, Primus FG: Radioimmunodetection of cancer with radioactive antibodies to carcinoembryonic antigen. Cancer Res 1980, 40:2984-2992.

38. Juweid ME, Sharkey RM, Behr T, Swayne LC, Rubin AD, Herskovic T, Hanley D, Markowitz A, Dunn R, Siegel J, Goldenberg DM: Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen. J Clin Oncol 1996, 14:1209-1217. 39. Juweid ME, Hajjar G, Swayne LC, Sharkey RM, Suleiman S, Herskovic T, Pereira M, Rubin AD, Goldenberg DM: Phase I/II trial of 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma. Cancer 1999, 85:1828-1842. 40. Juweid ME, Swayne L, Sharkey RM, Dunn R, Rubin A, Herskovic T, Goldenberg DM: Prospects of radioimmunotherapy in epithial ovarian cancer: results with 131I-labeled murine and humanized

569

MN-14 anti-carcinoembryonic antigen (CEA) monoclonal antibodies. Gynecologic Oncology 1997, 67:259-271. 41. Juweid M, Rubin A, Hajjar G, Stein R, Sharkey RM, Goldenberg DM: •• First clinical results of combined radioimmunotherapy (RAIT) and chemotherapy (CH) in patients with medullary thyroid cancer [abstract]. In Proceedings of the Endocrine Society’s 81st Annual Meeting: 1999 June 12–15; San Diego. Bethesda: Endocrine Society Press; 1999:434. The authors present the initial Phase I results of combining RIT with chemotherapy in medullary thyroid cancer. 42. Steffens MG, Boerman OC, DeMulder PHM, Oyen WJG, Buijs WCAM, • Witjes JA, van den Broek WJM, Oosterwijk-Wakka JC, Debruyne FMJ, Corstens FHM, Oosterwijk E: Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250. Clin Cancer Res 1999, in press. G250 shows the highest reported uptake (%ID/g) of RIT to metastatic tumors in patients demonstrated to date (0.5233%ID/g). 43. Goodwin DA, Meares CF: Editorial: pretargeted peptide imaging •• and therapy. Cancer Biotherapy Radiopharm 1999, 14:145-152. The authors present a comprehensive yet succinct review of the pretargeting approach to RIT. 44. Breitz HB, Weiden PL, Beaumier PL, Axworthy DB, Seiler C, Su FM, •• Graves S, Bryan K, Reno J: Clinical optimization of pretargeted radioimmunotherapy (PRITTM) with antibody-streptavidin conjugate and 90Y-DOTA-biotin. J Nucl Med 1999, in press. References [44••,45••] exploit the ultra-high-affinity interaction between biotin and streptavidin to deliver a radioisotope to a tumor and the clinical applications in lymphoma. 45. Breitz HB, Weiden PL, Appelbaum JW, Stone DM, Axworthy DB, •• Fisher DR, Press O, Abrams PG: Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin’s lymphoma: preliminary results [abstract]. J Nucl Med 1999, 40:19. See annotation [44••]. 46. Barbet J, Kraeber-Bodere F, Vuillez JP, Gautherot E, Rouvier E, Chatal JF: •• Pretargeting with the affinity enhancement system for radioimmunotherapy. Cancer Biother Radiopharm 1999, 14:153-167. The authors describe pretargeting with a bispecific antibody (anti-CEA–antiDTPA) followed by a radiolabeled bivalent hapten that forms a uniquely stable complex by cross-linking between the arms of the bispecific antibody on small-cell lung cancer and medullary thyroid tumors in patients. 47.

Adams GP: Improving the tumor specificity and retention of antibody-based molecules. In Vivo 1998, 12:11-22.

48. DeNardo SJ, DeNardo GL, DeNardo DG, Xiong CY, Shi XB, Winthrop MD, Kroger LA, Carter P: Antibody phage libraries for the next generation of tumor targeting radioimmunotherapeutics. Clin Cancer Res 1999, in press. 49. Kaminski MS, Vose J, Saleh M, Lister A, Knox S, Crowther D, Zelenetz AD, Colcher D, Wahl R: A multicenter phase II study of iodine-131 anti-B1 antibody in patients with chemotherapyrelapsed/refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 1997, 90:509. 50. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Stagg R, Kroll S, Tidmarsh G, Knox S, Vose J: Multicenter, phase III study of iodine-131 tositumomab (anti-B1 antibody) for chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 1998, 92:316. 51. Schrier DM, Stemmer SM, Johnson T, Kasliwal R, Lear J, Matthes S, Taffs S, Dufton C, Glenn SD, Butchko G et al.: High-dose 90Y Mxdiethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial. Cancer Res 1995, 55(suppl 23):5921-5924. 52. Denardo GL, O’Donnell RT, Shen S, Kroger LA, Yuan A, Meares CF, Kukis DL, Denardo SJ: Radiation dosimetry for 90Y-2IT-BAD-Lym-1 extrapolated from pharmacokinetics using 111I-2IT-BAD in patients with non-Hodgkin’s lymphoma. J Nucl Med 1999, in press.