Current Pharmaceutical Biotechnology - Volume 2, Issue 4, 2001

The non-Hodgkin's lymphomas are a diverse groups of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality. Conventional treatment for patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) includes radiation or chemotherapy. In addition, those with asymptomatic low-grade disease may follow a “watch and wait” approach. Single agent oral alkylating therapy and CVP (cyclophosphamide, vincristine, and prednisone) have become a mainstay of treatment for low-grade NHL. High intensity chemotherapy consisting of the anthracycline, doxorubicin along with cyclophosphamide, vincristine and prednisone (CHOP) is offered as standard treatment for intermediate-grade NHL. Following relapse, salvage therapy rarely results in long-term survival in patients with low-grade NHL. Up to 50percent of patients die within five years of first relapse. For patients with intermediate-grade NHL who relapse after or do not respond to first-line treatment, a range of combination regimens can be offered, composed of non-cross resistant drugs not typically used during first-line treatment. However, less than half of patients with intermediate-grade disease achieve prolonged disease-free survival. With today‘s’conventional treatments, cure is only a possibility for a minority of patients with intermediate-grade disease and a limited group of patients with indolent NHL who are diagnosed at early stages. Novel approaches to treatment are therefore needed. Monoclonal antibodies may fulfill this need, administered either as single agents or in conjunction with conventional cytotoxic approaches. The task now lies in determining how best to use this new modality, with the hope of bringing a cure to a greater number of patients.

The potential of antibodies as “magic bullets” for cancer therapy has been appreciated for nearly a century. During the past 25 years, various scientific developments have made possible the production of unlimited quantities of clinical-grade murine, chimeric, and humanized monoclonal antibodies (MoAbs). Intact, unconjugated MoAbs may: [1] produce anticancer effects through the immune system on the basis of interactions between the Fc portion of antibody and complement proteins and / or effector cells [2] induce regulatory effects by neutralizing circulating ligands or blocking cell membrane receptors, thereby interfering with ligand / receptor interactions and signal transduction [3] serve as immunogens for anti-cancer vaccines through the anti-idiotype-network cascade. Conjugated MoAbs can serve as carriers of other agents such as radioisotopes, natural toxins, chemotherapy drugs, cytokines, and immune cells. Important aspects of the antigenic target are the degree to which it is tumor-specific or tumor-associated, whether it internalizes or not, whether it is shed, the density of expression, and the physiologic significance of the antigen to the target cell. The clinical foundation for antibody-mediated therapy was laid in the 1980s when investigators established the safety of antibody administration, defined certain predictable antibody-mediated toxicities, and confirmed that antibodies could reach tumor targets and produce antitumor effects. A major limitation of these early mouse monoclonal antibodies was overcome with the production of antibodies with varying degrees of humanization. In 1997 rituximab (RituxanÒ), a mouse-human chimeric anti-CD20, became the first MoAb approved by regulatory agencies for the treatment of a human malignancy.

Monoclonal antibodies (MAbs) have been used as therapeutic agents for many years. In 1997, Rituxan (IDEC-C2B8, rituximab, MabThera) became the first MAb to be approved by the FDA for a cancer indication. Rituxan served to heighten interest in the therapeutic applications of MAbs. Herceptin (for patients with breast cancer) and Mylotarg (for patients with acute myeloid leukemia) were approved shortly thereafter. Literally dozens of antibodies are currently under investigation for a variety of malignant and non-neoplastic indications. Rituxan is effective in patients with low-grade or follicular, relapsed or refractory non-Hodgkin's lymphoma (NHL). The response rate and time to progression (responders) are in the 50percent and 13 months range, respectively. It is also active in intermediate-grade NHL where a large randomized study, in combination with CHOP chemotherapy, has shown a statistically significant increase in complete response (CR) rate (75percent vs. 60percent), prolongation of 1 year event-free survival (69percent vs. 49percent) and of overall survival (83percent vs. 68percent) as compared to CHOP alone. This marks the first time that any agent has shown results superior to CHOP, the curative gold standard for this type of NHL. Other promising antibodies under clinical investigation include: Hu1D10; Anti CD19, 22, 52, and anti-Id antibodies. The safety profile, clinical activity, and mechanism of action of these MAbs make them ideal candidates for combination with chemotherapy or biologicals. Over the next few years, we will see very significant therapeutic advances emerge as this important research yields additional clinical results.

To arm monoclonal antibodies (MAbs) with the power to kill malignant cells, they have been connected to toxins to create chimeric proteins called immunotoxins. Conventional immunotoxins contain a MAb chemically conjugated to a toxin which is mutated or chemically modified to minimize binding to normal cells. Examples include anti-B4-blocked ricin, targeting CD5, and RFB4-deglycosylated ricin A chain, targeting CD22. Conventional immunotoxins are capable of inducing responses in patients with hematologic malignancies, with dose-limiting toxicities being vascular leak syndrome, thrombocytopenia, and hepatic damage. Newer immunotoxins contain a recombinant ligand, either the variable domains (Fv) of a MAb, or a growth factor, fused to a truncated bacterial toxin. Bacterial toxins commonly used for this purpose include diphtheria toxin and Pseudomonas exotoxin. DAB389IL2 (Ontak) is a recently approved growth factor fusion toxin containing human interleukin-2 and diphtheria toxin and is effective in chemotherapy-resistant cutaneous T-cell lymphoma. Anti-Tac(Fv)-PE38 (LMB-2) and RFB4(dsFv)-PE38 (BL22) are two recombinant immunotoxins, targeting CD25 and CD22, respectively, in which Fvs of MAbs targeting these antigens are fused to truncated Pseudomonas exotoxin. Both LMB-2 and BL22 have exhibited clinical activity in patients with hematologic malignancies, with less vascular leak syndrome and probably less immunogenicity than the larger conventional immunotoxin conjugates. New recombinant immunotoxins are currently being engineered and developed to target other hematologic and solid tumor antigens.

Much progress has been made in the development and implementation of radionuclide-carrying antibody therapy (radioimmunotherapy or RIT) of non-Hodgkin's lymphomas (NHL) in the past decade. Response rates have generally exceeded 60 percent for nonmyeloablative single dose RIT (85percent - 100percent for myeloablative) in patients who have relapsed after primary therapy. It is also encouraging that the duration of such responses has often been greater than the response to the last chemotherapeutic regimen administered. These results, as well as a favorable toxicity profile, have resulted in the successful earlier and more widespread use of this new therapeutic modality. Although unlabeled antibody therapy alone has had a positive impact on the treatment of NHL, the response rates for RIT have been higher than (sometimes nearly double) those for unlabeled antibody therapy. This has been demonstrated in trials that have directly compared radiolabeled antibody with unlabeled antibody, as well as in separate trials for similar patient groups. Use of radionuclides in conjunction with antibodies adds transient marrow suppression and a small risk of second malignancy over unlabeled antibody therapy. However, the toxicity from a single course of RIT is very favorable compared to chemotherapy. Despite the enormous progress of RIT, much remains to be learned to fully optimize the role of this exciting modality in the treatment of NHL.

Zevalin (ibritumomab tiuxetan, IDEC-Y2B8) is a murine IgG1 kappa monoclonal antibody conjugated to tiuxetan (MXDTPA) that chelates Yttrium or Indium and is directed against the CD 20 molecules of B lymphocytes. Phase I studies have determined the optimal dose of pretreatment rituximab to be 250 mg / m2 seven days prior and immediately prior to the administration of Zevalin. Phase I / II data have determined the dose of 0.4 mCi / kg to be the maximum tolerated dose (MTD) for patients with platelet counts > 150,000 and < 25percent bone marrow involvement with NHL. The dose of 0.3 mCi / kg is the MTD in patients with platelet counts between 100,000-149,000. Toxicity is primarily hematologic, transient, and reversible. Dosimetry has been completed using 111In-2B8. Results to date demonstrate that, at the above doses, no patients exceeded the protocol-prescribed organ maximum dose of 2,000 cGy or red marrow maximum dose of 300 cGy. Therefore, future use will not require pretreatment dosimetry. Zevalin contains a pure beta-emitting isotope no protective patient or staff isolation procedures are required. A randomized Phase III trial has been completed, comparing Zevalin with a standard dose of rituximab (375 mg / m2 q week for four weeks) in patients with relapsed indolent or follicular transformed NHL. The overall response rate (ORR) was 80 percent in the Zevalin arm compared to 56 percent (p = 0.002) in the rituximab arm. The CR was 30 percent vs 16 percent (p=0.04). A nonrandomized trial in patients refractory to rituximab demonstrated an ORR of 74 percent and a CR rate of 15 percent. A Phase II study of a reduced dose of Zevalin in patients with mild thrombocytopenia demonstrated an ORR of 67 percent and a 33 percent CR rate. Zevalin is safe and effective in patients with relapsed or refractory NHL, even in patients refractory to prior rituximab therapy.

A number of therapeutic agents in nuclear medicine are currently attracting considerable interest, including several for the treatment of hematologic and nonhematologic malignancies. A knowledge of the radiation dose received by different organs in the body is essential to the optimization of the therapy for each patient one wants to maximize the dose to the malignant tissue while minimizing the dose to critical healthy tissues and avoiding any toxic response therein. In this paper, current methods for calculating radiation doses will be discussed and evaluated. In almost all nuclear medicine therapy, and particularly in this application, dose to the active marrow is of paramount concern. Specific focus on current bone marrow dose models and their ability to predict observed marrow toxicity in patient populations to date will be discussed. The paper will focus on current and possible future dosimetry practice in therapeutic nuclear medicine, particularly as regards the treatment of hematologic malignancies.

The development of antibody-based therapies for the treatment of both acute and chronic leukemias have undoubtedly been one of the most important advances in the treatment of leukemia. The importance of these novel agents lies not only in their unique mechanisms of action, but also their improved side effect profile which allows patients of advanced age or with significant co-morbid medical conditions to receive potentially beneficial therapies. Advances in therapeutic applications of monoclonal antibodies have come from a greater understanding of the biological characteristics of the antibody, as well as the target antigen, both of which impact the potential efficacy of a particular antibody. In the following review we will discuss the clinical development and potential roles of monoclonal antibodies in the treatment of both acute and chronic leukemias.

The approval of monoclonal antibodies for therapy of hematologic malignacies (Rituxan, Mylotarg, Campath) renewed the interest in antibodies as potential new treatment options for cancer patients. Antibodies are effective in inhibiting tumor cell growth , inducing apoptosis, and activating host effector mechanisms for tumor cell killing. Monoclonal antibodies can be clinically effective as monotherapy, as targeting agents delivering either potent cytotoxic drugs or radionuclides as well as in combination with conventional chemotherapies. Advances in antibody engineering provided new capabilities to reduce immunogenicity, alter half life, increase effector functions, and increase tumor targeting for optimal therapeutic modalities requiring chronic dosing regimens. During the next decade, as new tumor-specific surface antigens are discovered and the linkage between genes and function is better understood, new targets will be identified for regulating tumor cell growth by engineered antibodies with agonist or antagonist activity. Additionally, antibody engineering will allow for more efficient radionuclide or cytotoxic drug targeting or lead to more selective activation of relevant host effector mechanisms, leading to a safe and effective therapy of cancer.