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The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic malignancies are ideally suited to targeted α-particle therapy (TAT) due to easy accessibility of malignant cells in blood, bone marrow, lymph nodes, and spleen as well as their radiosensitivity. Most clinical trials using α-particle therapy for hematologic malignancies have focused on acute myeloid leukemia (AML); however, preclinical studies have shown activity against other diseases such as non-Hodgkin's lymphoma and multiple myeloma. To date, the short-lived radionuclide bismuth-213 (213Bi) and its parent actinium-225 (225Ac) have been used clinically, but trials with astatinie-211 (211At) have recently begun, and thorium-227 (227Th) has shown promising preclinical results. Lintuzumab is a humanized monoclonal antibody that targets the cell surface antigen CD33, which is expressed on the vast majority of AML cells. Initial studies showed that 213Bi-labeled lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. An initial phase I trial demonstrated that a single infusion of 225Ac-lintuzumab could be given safely at doses upto 111 kBq/kg with antileukemic activity across all dose levels. A second phase I study showed that fractionated-dose 225Ac-lintuzumab could be safely combined with low-dose cytarabine and produced objective responses in 28% of older patients with untreated AML. In a phase II study, treatment with 225Ac-lintuzumab monotherapy for a similar patient population resulted in remission in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. Additionally, TAT may be useful in intensifying antileukemic therapy prior to hematopoietic cell transplantation, and pretargeting strategies offer the possibility for improved tumor-to-normal organ dose ratios.

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.

Methods to generate monoclonal antibodies to antigens of neoplastic cells have revolutionized our understanding of cancer cell growth and differentiation, diagnosis, and treatment. Monoclonal antibodies derived by immunizing animals (mostly mice) with mammalian cells or molecules have been critical reagents for the discovery and characterization of many key molecules involved in the behavior of neoplastic cells. Now, over 30 years later, monoclonal antibodies are widely used in the differential diagnosis of cancer and are key elements in the treatment of many forms of cancer. This review will focus on the roles that monoclonal antibodies play in the treatment of hematological malignancies. In particular, we will focus on acute myeloid leukemia and mature B-cell neoplasms.

Purpose Lintuzumab (HuM195) is an unconjugated humanized murine monoclonal antibody directed against the cell surface myelomonocytic differentiation antigen CD33. In this study, the efficacy of lintuzumab in combination with induction chemotherapy was compared with chemotherapy alone in adults with first relapsed or primary refractory acute myeloid leukemia (AML). Patients and Methods Patients with relapsed or primary resistant AML (duration of first response, zero to 12 months) were randomly assigned to receive either mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 g/m2 daily for 6 days (MEC) in combination with lintuzumab 12 mg/m2, or MEC alone. Overall response, defined as the rate of complete remission (CR) and CR with incomplete platelet recovery (CRp), was the primary end point of the study, with additional analyses of survival time and toxicity. Results A total of 191 patients were randomly assigned from November 1999 to April 2001. The percent CR plus CRp with MEC plus lintuzumab was 36% v 28% in patients treated with MEC alone (P = .28). The overall median survival was 156 days and was not different in the two arms of the study. Apart from mild antibody infusion–related toxicities (fever, chills, and hypotension), no differences in chemotherapy-related adverse effects, including hepatic and cardiac dysfunction, were observed with the addition of lintuzumab to induction chemotherapy. Conclusion The addition of lintuzumab to salvage induction chemotherapy was safe, but did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML.

The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.

HuM195 is a humanized, unconjugated, anti-CD33 monoclonal antibody. Fifty adult patients with relapsed or refractory AML were randomized to receive HuM195 at a dose of 12 or 36 mg/m(2) by intravenous infusion over 4 h on days 1-4 and 15-18. Patients with stable or responding disease received two additional cycles on days 29-32 and 43-46. HuM195 was given as first salvage therapy in 24 patients and as second or subsequent salvage therapy in 26 patients. Pretreatment blast percentage in the marrow was between 5 and 30% in 20 patients with the others having blast counts greater than 30%. The median age of patients was 62 years (range 26-86) and CD33 was detected in 95% of patients for whom immunophenotyping was available. Of 49 evaluable patients, two complete and one partial remission were observed. All three responses were in patients treated at the 12 mg/m(2) dose level and all had baseline blast percentages less than 30%. Decreases in blast counts ranging from 30 to 74% were seen in nine additional patients. Infusion-related events of fever and chills occurred in the majority of patients and were generally mild and primarily related to the first dose of antibody. No hepatic, renal or cardiac toxicities were observed and other adverse events such as nausea, vomiting, mucositis and diarrhea were uncommon or felt to be unrelated to HuM195. In addition, anti-HuM195 responses were not detected. HuM195 as a single agent has minimal, but observable, anti-leukemic activity in patients with relapsed or refractory AML and activity is confined to patients with low burden disease. No significant differences in clinical efficacy or toxicity were seen between the two dose levels of antibody. HuM195 was well tolerated with infusion-related fevers and chills the predominant toxicities seen. Meaningful clinical efficacy of this unconjugated monoclonal antibody may be realized only in patients with minimal residual disease, or in combination with chemotherapy.

A number of new agents in acute myeloid leukemia (AML) have held much promise in recent years, but most have failed to change the therapeutic landscape. Indeed, with the exception of gemtuzumab ozogamicin (which was subsequently voluntarily withdrawn from the commercial market), no new agent has been approved for acute myeloid leukemia (AML) beyond the 7 + 3 regimen, which was has been in use for over 40 years. This review touches upon the potential reasons for these failures and explores the newer therapeutic approaches being pursued in AML.

Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body, 1.1 to 6.1 rad/mCi was delivered to the plasma, and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated, with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.

Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab ozogamicin, and alemtuzumab are US Food and Drug Administration-approved for treatment of B-cell lymphomas, acute myeloid leukemia, and chronic lymphocytic leukemia, respectively. Multiple monoclonal antibodies directed against new and not-so-new cellular antigens are undergoing development and investigation all over the world. Most of these new compounds have undergone primatization or humanization, improving their specificity and decreasing their antigenicity when compared to earlier murine or chimeric products. This review will focus on three major aspects of monoclonal antibody therapy: 1) new therapeutic approaches with currently approved agents; 2) preclinical and clinical experience accumulated on new agents in the last few years; discussion will include available phase I, II, and III data on ofatumumab, epratuzumab, CMC-544, HeFi-1, SGN-30, MDX-060, HuM195 (lintuzumab), galiximab, lumiliximab, zanolimumab, and apolizumab; and 3) the role of naked and radiolabeled monoclonal antibodies in the hematopoietic stem cell transplantation setting.