Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section D – Preventing and Treating Cancer

Chapter 34 – Therapeutic Antibodies and Immunologic Conjugates

Nai-Kong V. Cheung




Because of their tumor selectivity, monoclonal antibodies offer exceptional opportunities for targeted therapy.



As naked antibodies, they kill tumors by receptor blockade and by actively inducing apoptosis.



Tumor cytotoxicity is mediated in the presence of white cells by activating antibody-dependent cell-mediated cytotoxicity; and in the presence of serum, it is mediated by complement.



The effector functions of antibodies can be greatly enhanced as immunoconjugates, which include radioimmunoconjugates, immunocytokines, immunotoxins, immunoenzymes, immunoliposomes, and cellular immunoconjugates.



Naked antibodies can, on occasion, have overlapping toxicity profiles with chemotherapy and radiation therapies.



Dose-limiting toxicities of immunoconjugates depend on the cytotoxic moiety (e.g., myelosuppression in radioimmunoconjugates) being used.



Antibodies are likely to be most beneficial at the time of minimal residual disease, especially when used in conjunction with standard therapy.



The following antibodies have been licensed by the FDA for specific cancers:



Alemtuzumab (Campath): β-chronic lymphocytic leukemia (CD52)



Bevacizumab (Avastin): colorectal cancer (VEGF)



Cetuximab (Erbitux): colorectal cancer, head and neck cancer (EGFR)



Gemtuzumab ozogamicin (Mylotarg): acute myelogenous leukemia (calicheamicin, CD33)



Ibritumomab (Zevalin): non-Hodgkin's lymphoma (90Y, CD20)



Rituximab (Rituxan): non-Hodgkin's lymphoma (CD20)



Tositumomab (Bexxar): non-Hodgkin's lymphoma (131I, CD20)



Trastuzumab (Herceptin): breast cancer (HER2)



In the coming decade, other monoclonal antibodies that are currently in various phases of clinical trial as well as those approved for nononcologic indications could be added to the list. The prospects for further innovation in this maturing modality are highly favorable.


The clinical development of antibody therapy was accelerated by the introduction of the hybridoma technique in 1975 and the emergence of recombinant technology.[1] Through these innovations, individual plasma cells can be immortalized, and cloning of heavy and light chain repertoires from animals and humans is now possible. In the last three decades, monoclonal antibodies (MAb) have evolved from research tools to inclusion in a rapidly increasing list of licensed pharmaceuticals. They have generated excitement on many fronts and will likely play a pivotal role in the history of cancer medicine ( Box 34-1 ). The clinical utility of MAb for in vitro diagnosis and ex vivo manipulation of blood or stem cells is well recognized. Their role in the treatment and prophylaxis of graft versus host disease is detailed in Chapter 32 . The use of β-cell idiotype and anti-idiotypic antibodies as tumor vaccines is described in Chapter 6 . This chapter summarizes the application of therapeutic antitumor MAb and immunologic conjugates in cancer therapy.

Box 34-1 




1901: Nobel prize awarded to Emil von Behring for work on serum therapy in collaboration with Shibasaburo Kitasato



1908: Nobel prize awarded to Paul Ehrlich for his work on passive immunization



1927: Serotherapy of chronic myelogenous leukemia



1975: Hybridoma technique of Hans Kohler and Caesar Milstein (winners of 1986 Nobel prize)



1980: MAb therapy of lymphoma



1986: FDA approval of MAb as standard pharmaceuticals



1992: Murine 111In-anti-B72.3 for imaging colon and ovarian cancer



1997: Chimeric anti-CD20 (rituximab) for β-cell lymphoma



1998: Humanized anti-HER2 (trastuzumab) for breast cancer



1999: Humanized anti-CD33 immunotoxin for acute myelogenous leukemia



2001: Humanized anti-CD52 (alemtuzumab) for β-chronic lymphocytic leukemia



2002: 90Y-anti-CD20 (Ibritumomab) for β-cell lymphoma



2003: Murine 131I-anti-CD20 (tositumomab) for β-cell lymphoma



2004: Chimeric anti-EGFR (cetuximab) for colorectal cancer and head and neck cancer



2004: Humanized anti-VEGF (Bevacizumab) for colorectal cancer


Antitumor MAb can mediate highly effective tumoricidal functions both in vitro and in vivo ( Fig. 34-1 ). These include signaling through receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).


Figure 34-1  Effector mechanisms of monoclonal antibodies. ADEPT, antibody-directed enzyme prodrug therapy; ADCC, antibody dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain variable fragment.  (Modified from Carter P, Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118–129.)




Signaling by Receptor Cross-Linking and Receptor Blockade

When the antigen is a cell surface receptor, its clustering by multivalent MAb can induce apoptosis.[2] Apoptosis increases with hyper-cross-linking (e.g., CD20 target on lymphoma cells). [3] [4] [5] Both caspase dependent and independent programmed cell death pathways appear to be involved.[6] In AIDS-related lymphoma, anti-CD20 MAb diminishes p38MAPK signaling and Bcl-2 expression, while in non-AIDS-related lymphoma, signaling through CD20 inhibits AP-1 in addition to NF-κB, leading to downregulation of Bcl-XL, sensitizing lymphoma cells to chemotherapy.[7] Direct receptor blockade by MAb has also been reported for EGF-R1[8] and HER-2 (EFG-R2),[9] leading to upregulation of the BH3-only protein Bnip3L, thereby sensitizing tumor cells to chemotherapy.[10] MAb inhibition of VEGF-R1[11] or VEGF-R2[12] can also enhance the efficacy of chemotherapy.

Cytophilic MAb and ADCC

The Fc region of IgG MAb interacts with both activating and inhibitory Fc receptors (FcγR).[13] In humans, there are four activating FcγRs: FcγRI (CD64) is a high-affinity FcγR, whereas FcγRIIA(CD32A), FcγRIIIA (CD16A), and FcγRIIIB (CD16B) are low-affinity FcγRs. FcγRIIB (CD32B) is the only known inhibitory FcγR ( Table 34-1 ). All FcγRs (except FcγRIIIB) are transmembrane glycoproteins that are anchored on neutrophils by glycosylphosphatidylinositol. Activating FcγRs (with the exception of FcγRIIA) require the accessory g chain, which carries a cytoplasmic immunoreceptor tyrosine-based activation motif for activation. Immunoreceptor tyrosine-based activation motif becomes tyrosine phosphorylated by members of the Src-kinase family with subsequent recruitment of SH2-containing kinases. These events lead to the activation of phosphatidylinositol 3-kinase and phospholipase-Cγ, followed by protein kinase C activation and sustained calcium elevation.[13] These biochemical cascades trigger phagocytosis, degranulation, cytokine release, and antibody-dependent cell-mediated cytotoxicity. In sharp contrast to activating FcγRs, FcγRIIB is a single-chain receptor that carries the immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic domain. Engagement of this inhibitory receptor downregulates both biochemical and cellular functions. The ratio of activating to inhibitory FcγRs on immune cells, such as dendritic cells, macrophages, and neutrophils, can greatly influence the antitumor properties of MAb.

Table 34-1   -- Properties of IgG Fc Receptors[13]

Fc Receptor


Affinity for hIgG

Distribution on WBC




















PMN, MONO, MΦ, β-cell

















A, activating; DC, dendritic cells; hIgG, human IgG; I, inhibiting; MONO, monocytes; MΦ, macrophages; PMN, neutrophils; WBC, white blood cells.



Prefers antibody-antigen complex.



Inflammatory mediators (interferon-γ or C5a) increase activating FcγRs and downregulate inhibitory FcγRIIB, while IL-4, IL-10, and TGF-β upregulate FcγRIIB, thereby raising the thresholds for cell activation. Removing the inhibitory signals by FcγRIIB-blocking antibodies have shown efficacy in preclinical models.[13] This is particularly relevant for cross-presentation of antigens that are acquiredendocytically through Fc receptors on dendritic cells during the induction of tumor-specific T-cell responses.[14] In addition to these FcγRs, a unique class of Fc receptor called FcRB (Brambell)/FcRn (neonatal) is found on endothelial cells and regulates antibody catabolism.[15] Although most therapeutic antibodies have been primarily IgGs, both IgA1 and IgA2 can also mediate efficient ADCC by binding to FcαRI (CD89) on human neutrophils and monocytes/macrophages.[16]

Certain cancer cells, such as colon carcinoma, lymphoma, leukemia, neuroblastoma, and melanoma, are effectively killed by natural killer (NK) lymphocytes, granulocytes, and activated monocytes in vitro in the presence of specific MAb. Depending on the affinity of the MAb for the individual FcγR, both NK cells (carrying FcγRII and FcγRIII) and neutrophils (bearing all three FcγRs) can mediate efficient ADCC. Because of the high affinity, FcγRI is generally occupied by monomeric IgG in human plasma. Human IgG subclasses (IgG1, IgG2, IgG3, and IgG4) have differential affinity for FcγRII and FcγRIII. Chimeric or humanized IgG1 antibodies (e.g., Lym-1 specific for HLA-DR and ch14.18 for GD2) exploit FcγRIII for lymphocyte ADCC while using FcγRII for myeloid ADCC. [17] [18] Among the four IgG subclasses, IgG2 has the lowest affinity for the inhibitory receptor FcγRIIB.[13] Mouse IgG3 (e.g., 3F8 specific for GD2) can engage both FcγRII and FcγRIII in ADCC,[19] despite its low affinity for human FcγRs. The correlation of patient FCGR2A [20] [21] and FCGR3A polymorphism [21] [22] with clinical responses to MAb suggests that affinity for Fc receptor can influence antitumor responses in patients. In addition to FcγRs, adhesion molecules are critical for MAb-mediated ADCC. These molecules include CR3 (CD11b/Cd18), [17] [18] [19] plus CD66b[17] for neutrophil ADCC and LFA-1 (CD11α/CD18) for lymphocyte ADCC.[23] Because cytokines can increase the expression of adhesion molecules, GM-CSF or interferon-γ has been used to activate granulocyte ADCC, [18] [24] [25] [26] and IL-2 has been used similarly for lymphocyte ADCC. [27] [28] Furthermore, because both GM-CSF and IL-2 expand the effector cell pools, they can have additional benefits in tumor therapy. Optimal combinations of MAb and cytokines in the appropriate clinical setting are being explored. [29] [30] [31]

Complement Activation

IgG initiates the classical complement cascade by binding C1q to its CH2 domain. C1q is more avid for human IgG1 and IgG3 than for IgG2 and has no affinity for IgG4.[32] CDC potency of individual MAbs is also correlated with its slow off-rate.[33] Although some tumor cell lines (e.g., lymphoma and neuroblastoma) are sensitive to CDC, many are resistant to complement because of anticomplement surface proteins such as decay-accelerating factor (DAF, CD55), [34] [35] [36] homologous restriction factor (CD59), [34] [37] [38] and membrane cofactor protein (CD46). [35] [36] [37] [39] The effect of complement activation extends beyond direct tumor lysis. Following complement activation, tumor-bound C3b is cleaved rapidly by plasma protease factor I to iC3b. Through CR3 (Mac-1 or αMβ2-integrin) and CR4 (CD11c/CD18, αXβ2-integrin) receptors on leukocytes, tumor cells are opsonized.[40] C3a and C5a, by-products of complement activation, are also potent mediators of inflammation[41]and are chemotactic for phagocytic leukocytes, drawing them to the tumor sites. C5a can also downregulate the inhibitory receptor FcγRIIB[13] or induce secondary cytokines to increase vascular permeability for both MAb and effector cells.


Lymphoma and Leukemia

In 1997, the anti-CD20 chimeric antibody rituximab became the first MAb to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer ( Table 34-2 ). In a single-arm multicenter study of 166 patients with relapsed or refractory, low-grade, or follicular non-Hodgkin's lymphoma (NHL), rituximab at a dose of 375 mg/m2 four times weekly produced an overall response (OR) rate of 48%, a complete response (CR) rate of 6%, and a partial response (PR) rate of 42%. Median time to progression in responders was 13.1 months.[42] In this study, rituximab demonstrated activity in chemoresistant disease (29%) and in patients relapsing after anthracycline therapy (51%). FDA approval was later expanded to include patients with bulky disease, retreatment of responders, and an extended treatment schedule of eight infusions. For most patients, rituximab was well tolerated.[43] Severe adverse events that were thought to be secondary to complement activation often occurred with the first infusion,[44] especially if there were high numbers of circulating tumor cells. These infusion-related reactions usually appeared 30 to 120 minutes after MAb injection and typically were associated with severe cardiopulmonary events, with deaths (<0.1%) occurring within 24 hours. β-cell depletion occurred in most patients, although serum IgG level remained normal for 12 months or longer without increased incidence of infection.[42] Severe mucocutaneous reactions occurred rarely (0.07%), resulting in some fatalities.

Table 34-2   -- Naked MAb for Cancer Therapy



Antibody Form


Effector Function/Molecule

Drug Status






Campath: Licensed





Neutralizing VEGF

Avastin: Licensed





ADCC, CDC; interrupts signaling pathways

Erbitux: Licensed





ADCC, CDC; interrupts signaling pathways

Rituxan: Licensed




Breast cancer

ADCC, CDC, receptor blockade

Herceptin: Licensed






Phase II






Phase II/III





ADCC, CDC; interrupts signaling pathways

Phase III

ADCC, antibody-dependent cell-mediated cytotoxicity; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; APL, acute promyelocytic leukemia; CDC, complement-dependent cytotoxicity; CRC, colorectal cancer; ch, chimeric; CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; H & N, head and neck cancer; hu, humanized; Ig, immunoglobulin; Licensed, licensed by the FDA; MAb, monoclonal antibody; MDS, myelodysplastic syndrome; NB, neuroblastoma; NHL, non-Hodgkin's lymphoma; PLL, prolymphocytic leukemia; VEGF, vascular endothelial growth factor.




Because of its chemosensitization, rituximab was tested in diffuse large β-cell NHL. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) plus rituximab was superior (76% CR, 69% progression-free survival [PFS], 83% overall survival [OS]) to CHOP alone (60%, 49%, and 68%, respectively).[45] In a randomized trial of 399 elderly subjects with previously untreated diffuse large β-cell lymphoma, CHOP plus rituximab compared to CHOP produced an OR of 76% compared to 63% and a 2-year OS of 70% compared to 57%, respectively.[46] Other antibodies in active clinical trials included epratuzumab (huIgG1 anti-CD22) for NHL, as single agents [47] [48] or in combination with rituximab,[49] and SGN-30 (chIgG1 anti-CD30) for Hodgkin's disease.[50]

Campath-1H (Alemtuzumab), a humanized rat IgG1 anti-CD52 MAb, has activity against recurrent chronic lymphocytic leukemia and T-cell prolymphocytic leukemia. [51] [52] In an international phase II study involving 21 centers (n=93 patients), Campath-1H was administered at 30 mg three times weekly for a maximum of 12 weeks to patients with relapsed or refractory β-cell chronic lymphocytic leukemia who had previously failed fludarabine therapy. OR was 33% (CR: 2%, PR: 31%). The median times to response and progression were 1.5 and 4.7 months, respectively, and median survival was 16 months. Grade 3 or 4 infections were reported in 26.9% of patients.[53] On the basis of this study, the FDA approved Campath-1H. Other clinical trials have also reported opportunistic infections, including bacterial sepsis and viral infections, as well as marrow aplasia following Campath-1H treatment. [52] [54]

In myeloid leukemia, the addition of lintuzumab (huM195, IgG1, anti-CD33) 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.[55]

Solid Tumors

Trastuzumab (Herceptin) is a humanized MAb against the receptor tyrosine kinase ERBB2 (also known as HER-2/NEU) on breast cancer cells. It can mediate a diverse spectrum of antitumor effector mechanisms. Besides CDC and ADCC, it can induce HER-2 protein downregulation, prevent HER-2-containing heterodimer formation, initiate G1 arrest, induce p27, prevent HER-2 cleavage, and inhibit angiogenesis.[56] The application of trastuzumab in metastatic breast cancer achieved OR of 15% (3.6% CR, 11.7% PR, n=222) with median response duration of 9.2 months and OS at 13 months.[57] Its efficacy in patients with recurrent or refractory ovarian cancer was limited by the low expression of HER-2 among these patients.[58] On the basis of its synergy with chemotherapy in vitro, [59] [60]trastuzumab was tested in a large phase III trial of 469 patients with breast cancer, in which its combination with chemotherapy produced a longer median response duration (9.1 versus 6.1 months), higher OR (50% versus 32%), and lower death rate at 1 year (22% versus 33%)[61] than chemotherapy alone. However, there was a significant increase in cardiotoxicity. On the basis of this trial, the FDA approved the use of trastuzumab and paclitaxel as a first-line treatment of HER-2-overexpressing metastatic breast cancer. Subsequent studies showed that one year of treatment with trastuzumab after adjuvant chemotherapy significantly improved disease-free survival among women with HER-2-positive breast cancer (either node-negative or node-positive) after locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy.[62] When combined with paclitaxel after doxorubicin and cyclophosphamide, trastuzumab also improved outcomes among women with surgically removed HER-2-positive breast cancer.[63]

Cetuximab (chIgG1 anti-EGFR) is another FDA-approved antibody designed to induce receptor blockade. It showed activity when given alone or when combined with irinotecan in patients with colorectal cancer (CRC).[64] In 346 patients with metastatic CRC that was refractory to irinotecan, oxaliplatin, and fluoropyrimidines, the overall response was approximately 12%.[65] An acneiform rash occurred in 82.9% of patients; a grade 3 rash was observed in 4.9%. Response and survival correlated strongly with the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. Neither EGFR kinase domain mutations nor EGFR gene amplification appeared to be essential for response to cetuximab in this setting. When combined with radiotherapy for squamous cell carcinoma of head and neck (H&N), cetuximab improved the duration of locoregional control from 14.9 to 24.4 months, increased OS from 29.3 to 49 months, and improved PFS.[66] Except for the known acneiform rash and infusion reactions due to cetuximab, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. In phase I/II combinations with chemotherapy, cetuximab had activity for both H&N[67] and CRC.[65] In a phase III randomized study, cetuximab plus cisplatin significantly improved response but not PFS or OS among patients with metastatic/recurrent H&N cancer.[68] The addition of cetuximab to chemotherapy for non-small-cell lung cancer showed only slight benefit.[69] Panitumumab, a fully human antibody that is specific for EGFR generated by using human IgG-transgenic mouse technology, also showed promise in phase II/III clinical trials.[70]

Despite initial enthusiasm,[71] adjuvant therapy with edrecolomab (17–1A, Panorex), a mouse IgG2a antibody specific for EpCAM on malignant and normal epithelial cells, did not improve DFS or OS in subsequent phase III studies in CRC. [72] [73] Even with the lack of clinical efficacy, anti-idiotype network and T-cell responses against antibody-modified tumors were found. [74] [75] Oregovomab (MAb B43.13, anti-CA125), a murine IgG1 antibody for ovarian cancer, did not improve time to relapse in a phase III randomized trial of 145 patients.[76] A correlation of improved survival and human antimouse antibody (HAMA)/idiotype network response was of biologic interest.[77]

Among the ganglioside antigens on neuroectodermal tumors, GD3 (MAb R24 for melanoma)[78] and GD2 (MAb 3F8 and ch14.18 for neuroblastoma) [79] [80] have been tested clinically. GD2 is present on a variety of solid tumors in addition to neuroblastoma, including osteosarcoma, retinoblastoma, some soft-tissue sarcomas, and brain tumors. Although the clinical effectiveness of anti-GD2 MAb for soft-tissue disease was modest, response of microscopic marrow disease was consistent. [31] [81] Clinical development of anti-GD2 MAb was limited by its pain side effects, precluding dose escalation. At current doses, optimal application of anti-GD2 antibody is at the time of minimal residual disease. [82] [83] An association of HAMA response and favorable patient outcome plus the induction of Ab2 and Ab3 through the idiotype network has also implicated a potential role of the host immune response in maintaining clinical remission. [84] [85]

Complications and Contraindications

Toxicities of MAb are in general manageable and self-limited. Common acute reactions include fever, chills, headache, nausea, fatigue, angioedema, urticaria, pruritus, blood pressure fluctuations, and bronchospasm. Lethal or irreversible side effects include cytokine release (antilymphocyte MAb) and complement activation (anti-CD20) syndromes,[44] immune suppression (anti-CD52), [52] [54] and cardiotoxicity (anti-HER-2).[61] A severe self-limited side effect is the pain syndrome from cross-reactivity of anti-GD2 MAb with peripheral pain fibers. [79] [80] Murine MAb induces HAMA responses that can alter the pharmacokinetic and pharmacodynamic properties of repeat MAb injections. HAMA is directed primarily to the murine Fc portion of the antibody, although anti-idiotypic responses have also been reported.[86] With chimeric, humanized, primatized, and human antibodies, immunogenicity is drastically reduced. [87] [88]


The clinical utility of naked MAb can be limited by both host (number and activity of effector cells, FcR polymorphism, and interference by inhibitory FcR) and tumor factors (antigen heterogeneity and complement regulatory proteins). Although the CDC and ADCC functions of naked MAb (see Fig. 35-1) can be improved by altering the Fc protein structure[87] or by modifying Fc-glycosylation, [89] [90] [91] substantial gains in clinical potentials of MAb can derive from immunoconjugates. These include (1) radioimmunoconjugates to deliver β- and α-emitters,[92] (2) immunocytokines to deliver cytokinesto tumor sites while minimizing systemic toxicities,[93] (3) immunotoxins,[94] (4) antibody-directed enzyme prodrug therapy (ADEPT) to pretarget enzymes to tumor sites for prodrug activation so that high local concentrations of active drugs are released without triggering systemic toxicities,[95] (5) immunoliposomes to deliver drugs or toxins,[96] and (6) bispecific MAb (pretargeted to tumor or by ex vivo arming) to direct cells or ligands selectively to tumor.[97] More recently, a multistep targeting strategy has been developed to enhance tumor to normal tissue ratios (see Fig. 35-1). [98] [99] The tumor is pretargeted using an antibody construct which has affinity for the tumor on one arm and for a radiolabeled hapten on the other arm (e.g., bispecific antibody or single-chain Fv-streptavidin systems). The radiolabeled hapten is administered after the antibody construct is cleared from circulation. Substantial improvements in the therapeutic index can be achieved. [92] [100] [101]


MAb have the potential to target and ablate tumors in radioimmunotherapy (RIT). Radioimaging can map the biodistribution of MAb and quantify the relative amounts of MAb deposited in various tissues and organs, thus allowing more precise radiation dose estimates in therapeutic studies. With the advent of single photon emission computed tomography and positron emission tomography, accurate dosimetry is readily achievable. In preclinical models, ablation of established xenografts is possible, although radiation damage to the marrow remains dose-limiting. For patients with lymphoma and leukemia, antitumor activity of RIT is highly reproducible, but major responses in solid tumors are rare. Unlike naked antibodies, the bystander effect of RIT from cross-firing of the radioisotopes accounts for most of the toxicities of radioimmunoconjugates, hence limiting their efficacy.

Choice of Radioiosotopes for Radioimmunoconjugates

Most clinical applications of RIT utilize β-emitting radioimmunoconjugates ( Table 34-3 ). β-Particles have a relatively long range (0.8 to 5 mm) and low linear energy transfer (approximately 0.2 keV/mm). This long range results in the delivery of radiation not only to the antigen-positive tumor cells, but also to antigen-negative tumor cells, as well as to the surrounding normal tissues. Thus, β-emitters can treat bulky diseases effectively but are not optimal for killing single cells or micrometastasis. Most early human studies of RIT have used iodine-131 (131I), a long-lived β-particle emitter. Because of its γ-particles emission, it is also suitable for dosimetry studies. However, this γ-particle emission poses a radio hazard at high treatment doses, necessitating patient isolation. In vivo dehalogenation can compromise tumor dose with subsequent thyroid damage from the released iodide. Yttrium-90 (90Y) is a pure β-emitter; its lack of γ-radiation allows outpatient treatment. However, 90Y has its limitations, including deposition in bone when dissociated from the MAb complex. Unlike 131I, which binds directly to tyrosine residues on the MAb, 90Y requires the coupling of a chemical chelator to the MAb. Furthermore, the lack of γ-emissions means that biodistribution and dosimetry studies of 90Y necessitate trace-labeling with indium-111 (111In), the biodistribution of which is not identical to that of 90Y. Besides 90Y, other β-emitters that have recently been explored include rhenium-186 (186Re), rhenium-188 (188Re), copper-67 (67Cu), and lutetium-177 (177Lu), but all have limitations.

Table 34-3   -- Choice of Radioisotopes for Radioimmunotherapy


Particle(s) Emitted

Half-Life Hours

Maximum Energy (keV)

Mean Range of α- or β-Particle Emission (mm)

Iodine-131 (131I)

β, γ




Yttrium-90 (90Y)





Copper-67 (67Cu)





Lutetium-177 (177Lu)





Rhenium-188 (188Re)

β, γ




Actinium-225 (225Ac)





Astatine-211 (211At)





Bismuth-213 (213Bi)







Alpha-particles are helium nuclei; when compared with β-particles, they have a shorter range (50 to 80 mm) and a higher linear energy transfer (approximately 100 keV/μm).[102] As few as one or two α-particles can destroy a target cell. Radioimmunotherapy using α-emitters should result in less nonspecific toxicity to normal bystanders as well as more efficient single-cell killing. This is ideal for controlling minimal residual disease. α-Particle-emitting isotopes such as astatine-211 and bismuth-213 have been tested in clinical trials. 213Bi-HuM195 (anti-CD33) administered intravenously for AML[103] and 211At-8C16 administered intraventricularly or intrathecally for gliomas[104] have been well tolerated and produced clinical responses. The relative lack of extramedullary toxicities should encourage further development of this targeting technique for micrometastases or neoplasms on the surface of body compartments, such as ovarian cancer and leptomeningeal metastasis. [105] [106] [107]

Radiolabeled MAb for Lymphoma

In patient studies of RIT, sequestration of MAb in liver or spleen can compromise tumor delivery. To overcome uptake by the reticuloendothelial system, a large dose of naked anti-CD20 antibody is needed to reduce liver uptake before RIT ( Table 34-4 ).[108] In a three-component regimen (Zevalin), rituximab at 250 mg/m2 at the rate of 100 mg/h was first administered to clear peripheral blood B cells, followed within 4 hours by 111In-ibritumomab tiuxetan and 90Y-ibritumomab tiuxetan infusion. At 0.2 to 0.4 mCi/kg (7.4 to 15MBq/kg) of 90Y-ibritumomab, dosimetry data derived from four large trials showed median radiation absorbed doses of 7.4 Gy to spleen, 4.5 Gy to liver, 2.1 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image–derived method) to red marrow, and 0.57 Gy to total body, with a median effective blood half-life of 27h.[109] Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30% to 35%, 10% to 14%, and 3% to 8% of patients, respectively. Myelodysplasia and acute myelogenous leukemia (AML) were reported in 1% of patients 8 to 34 months after treatment.[110] Serious grade 3 and 4 toxicities occurred in 3% of patients, and life-threatening events occurred in 1% to 5%. Four weeks after therapy, no circulating B cells could be detected, and recovery began about 12 weeks after therapy, usually to normal limits by 9 months. Serum IgG and IgA remained unchanged throughout, while IgM dropped below normal and recovered by 6 months; 3.8% of patients developed HAMA or human antichimeric antibody. Among patients with relapsed or refractory NHL,[111] OR rate was 83% (37% CR and 40% PR). Median time to progression was 9.4 months. In a phase III randomized study, a single dose of 0.4 mCi/kg 90Y-ibritumomab (n=73) was more effective than rituximab, 375 mg/m2/week for 4 weeks in patients (n=70) with relapsed or refractory low-grade, follicular, or transformed NHL. [112] [113] This difference was statistically significant for OR (80% versus 56%), CR (30% versus 16%), and the probability of ≥6-month durable responses (64% versus 47%), respectively. In other studies, increasing the dose or dose intensity of rituximab has not produced a meaningful improvement in outcome.

Table 34-4   -- Radiolabeled MAb for Radioimmunotherapy

Antibody Status


Antibody Form





Tositumomab [114] [115] [116] [117] [118]







Ibritumomab [109] [110] [111]







hMN14[92] (Labetuzumab)






Phase I/II







Phase III







Phase III

CRC, colorectal cancer; hu, humanized; Ig, immunoglobulin; Licensed, licensed by the FDA; mu, murine; NHL, non-Hodgkin's lymphoma.




131I-tositumomab (Bexxar, anti-CD20) achieved 71% OR (34% CR) in a phase II trial (n=59) of chemotherapy-refractory/relapsed patients with NHL. In 17% of patients, HAMA was induced.[114] Using myeloablative doses of 280 to 785 mCi (calculated to deliver 25 to 72 Gy to critical organs), 30 of 36 patients (83%) achieved durable CR, with OS of 68% and PFS of 42% (median follow-up, 42 months).[115] [116] Hypothyroidism developed in 60% of patients 6 to 12 months after therapy, and secondary myelodysplastic syndrome/AML was reported in 2% to 5%. [116] [117] Similarly, myeloablative doses (10 to 31 Gy) of 131I-anti-CD37 MAb produced 84% CR and 11% PR in patients with NHL, with eight patients in continual remission 46 to 95 months after therapy. Extramedullary toxicities were mild at doses of less than 23 Gy, beyond which cardiopulmonary toxicity became dose-limiting.[118]

Because the β-cell antigen CD22 is internalized, anti-CD22 antibody may be more effective when used in RIT than in its naked form. 131I-epratuzumab (LL2, humanized anti-CD22),[119] 90Y-epratuzumab,[120] and 186Re-epratuzumab[121] have all shown antitumor activity against β-cell lymphoma. In addition, unlike anti-CD20, good biodistribution was achieved with a humanized antibody (hLL2) without the need for preinjection of unlabeled antibody. Other promising antigen systems for RIT include internalizing antigens such as CD19[122] and HLA-DR,[123] CR2,[124] CD37,[125], CD30,[126] and β-cell idiotypes.[127] In one study, HAMA response to the MAb Lym-1 appeared to correlate with improved survival.[128]

As part of autologous hematopoietic cell transplant conditioning for patients with NHL, cyclophosphamide and etoposide were combined with 131I-tositumomab[129] or 90Y-ibritumomab tiuxetan in one study.[130] In another study, carmustine, etoposide, cytarabine, and melphalan were combined with 131I-tositumomab.[131] There were no significant added toxicities from RIT, and the EFS and OS were highly favorable when compared to historical controls. In stem cell transplant for relapsed mantle cell lymphoma, 131I-tositumomab when added to high-dose etoposide plus cyclophosphamide also produced encouraging results.[132] The addition of RIT therapy to conventional conditioning regimens deserves to be explored further, especially among patients with high-risk aggressive lymphomas, mantle cell lymphoma, and relapsed follicular NHL.[133] Rituximab is an accepted treatment strategy for most patients with NHL.[134] However, most if not all patients eventually relapse and require further therapy. Although it can achieve a second response in follicular or low-grade NHL, resistance usually develops requiring switching to radioimmunotherapy with 131I-tositumomab or 90Y-ibritumomab.[135] The outcome for patients who are treated first with a radiolabeled antibody and then with an unconjugated antibody has not been evaluated. However, because of myelosuppression, patients might not tolerate other therapy after failing RIT. A general approach in NHL is to use rituximab after chemotherapy failure, followed by RIT if rituximab fails.

Radiolabeled MAb for Leukemia

Radiolabeled MAb targeted to lineage specific antigens have been safely administered to patients with leukemia.[136] 90Y-anti-CD25 was active in acute T-cell leukemia (2 CR, 7 PR among 16 evaluable patients),[137] and myelosuppression was the primary toxicity. 131I-anti-CD33 (AML, myelodysplastic syndrome [MDS], myeloblastic CML), [138] [139] 90Y-anti-CD33,[136] 131I-anti-CD45 (AML, acute lymphoblastic leukemia, MDS),[140] and 188Re-anti-CD66c (AML, ALL, CML)[141] all delivered significant radiation doses to the bone marrow and are particularly effective as part of a conditioning regimen for hematopoietic stem cell transplantation. Radioconjugates that emit α-particles (213Bi-anti-CD33 and 225Ac-anti-CD33) might be better suited for the treatment of small-volume disease. [142] [143]

Radioimmunotherapy of Solid Tumors

The antitumor activity of RIT in solid tumors is less impressive (see Table 34-4 ).[144] A number of radiolabeled MAb have been tested in phase I/II setting in CRC with modest clinical benefit: 131I-17-1A (specific for Ep-CAM), 131I-B72.3 (pancarcinoma), 131I-anti-CEA (carcinoembryonic antigen), 90Y-CC49 (a second-generation murine antibody of B72.3), and 131I-CC49 or 131I-A33, some at myeloablative doses (50 to 300 mCi/m2).[144] 131I-hMN-14 (humanized anti-CEA IgG at 60 mCi/m2) has been administered to patients in remission or with small-volume colorectal metastasis; the potential for long-term benefit will have to await formal randomized trials.[92] For breast cancer and ovarian cancer, RIT targets have included MUC1, B72.3, L6, CEA, and gp38, whereas in renal cell cancer, G250 has been the main antigen of interest.[144]

Intravenous anti-GD2 131I-3F8 was tested in children with metastatic neuroblastoma at high doses (6 to 28 mCi/kg).[145] Responses were seen in both soft-tissue masses and bone marrow. The use of myeloablative 131I-3F8 (20 mCi/kg) to consolidate remission was tested in 35 patients (>1 year of age) with newly diagnosed stage 4 neuroblastoma.[31] Extramedullary toxicities were limited to hypothyroidism, which occurred despite aggressive thyroid protection using potassium iodide, liothyronine (T3), and potassium perchlorate. Intrathecal and intraventricular administration for leptomeningeal carcinomatosis and intratumoral therapy of malignant brain tumors using 131I-81C6 (antitenascin MAb) have produced objective responses and prolonged patient survival. [146] [147] 211At-81C6 is an example of α-particle therapy for minimal residual disease in malignant glioma.[148] Intraventricular 131I-3F8[149] and 131I-8H9[150] are also being tested in RIT for leptomeningeal cancers in both children and adults, with highly favorable CSF to blood radiation dose ratios; among children with recurrent neuroblastoma metastasized to the CNS, long-term remissions have been achieved.[151]

Multistep Targeting or Pretargeting

To improve tumor uptake and reduce systemic toxicity, a multistep procedure that pretargets the antibody before the binding of the cytotoxic ligand to the tumor has been employed successfully.[152]Generally, a tumor-specific antibody is conjugated to a ligand binder, such as streptavidin or avidin (with high affinity for biotin), or a ligand-specific antibody (binding to metal chelators such as diethylenetriamine pentaacetic acid [DTPA] or 1,4,7,10-tetraacetic acid [DOTA]). [98] [153] In the first step, these antibody-streptavidin or F(ab′)2-streptavidin conjugates (172 to 200 kd) are allowed to localize to tumors in vivo, and any excess is cleared from the blood. A small radiolabeled ligand (or its biotinylated form) is then injected intravenously. The ligand penetrates tissues rapidly and, by virtue of the high affinity interaction, binds tightly to the antibody-conjugate at the tumor site. Unbound ligand is quickly excreted through the kidneys. Because of the short transit time of the toxic ligand (radionuclides or toxins), a substantial improvement in the therapeutic ratio is achievable without sacrificing the percent injected dose per gram in tumor.

Antibody pretargeting has improved tumor imaging for colorectal, lung, and medullary thyroid cancers, especially when positron emission tomography radioisotopes are used. Multistep targeting of 110 mCi/m2 of 90Y-DOTA was well tolerated except for dose-limiting gastrointestinal toxicity that was thought to be related to MAb NT-LU-10 cross-reactivity with the gut.[154] Delayed renal toxicity was also observed. A similar approach that was applied to MAb CC49 in GI cancer[155] and anti-CD20 MAb in NHL [156] [157] achieved tumor doses of 0.289 Gy/mCi and 0.26 Gy/mCi, respectively, although the tumor-to-kidney dose ratio was less than 2.5. A three-step approach, which used biotinylated MAb, followed by avidin/streptavidin and then by biotinylated radiometal-chelate, was also applied to glioma with encouraging results. [100] [158] The bispecific antibody pretargeting system takes advantage of a bivalent hapten that binds to the two arms of a tumor-localizing bispecific antibody.[92] When anti-CEA bispecific antibody was tested in patients with SCLC[159] and in patients with medullary thyroid carcinoma, [160] [161] an average tumor dose of 0.192 Gy/mCi was achieved, accompanied by tumor stabilization in 45% of patients. Building on these early results, clinical studies combining with chemotherapy are under way.[162] Furthermore, pretargeting concepts may be potentially useful in targeting small ligands in addition to radioisotopes.


Cell-mediated cytotoxicity has been highly effective against tumors in vitro and in animal models. Immunocytokines [93] [163] have shown remarkable success in activating and redirecting effectors to human tumors. Most of these studies have focused on NK, natural killer T, or T cells[93] and granulocytes.[18] Antibody-IL-2 immunocytokine can eradicate metastatic murine neuroblastoma while inducing long-term antitumor immunity. [93] [163] Following initial successes with IL-2 immunocytokine, constructs containing other cytokines also have been tested with encouraging results.[93] These include IL-12, tumor necrosis factor, and lymphotoxin. This emerging technology has been successfully applied to a number of antigens and tumor models, including GD2, human epithelial cell adhesion molecule (hEpCAM), CEA, EGF-R, HER2, folate receptor, and β-cell idiotype. More recently, the combination of a plasmid DNA vaccine and IL-2 immunocytokine in the mouse model was shown to be more effective than when either one was administered alone.[164] KS-IL-2 (anticolorectal CA) and 14.18-IL-2 (anti-GD2) are both in clinical trials; their toxicity profiles are generally acceptable, but clinical efficacy has yet to be established.


Ribosome-inactivating toxins can be potent cancer drugs. One major limitation is the lack of tumor selectivity.[165] Two-chain toxins (e.g., ricin and diphtheria toxin [DT]) utilize their B chain for cell-binding and their A chain for inhibition of protein synthesis; other toxins (e.g., Pseudomonas exotoxin [PE], Pokeweed antiviral protein, and gelonin) have a built-in receptor for cell attachment. When conjugated to MAb, they become immunotoxins. These toxins can be genetically modified for MAb conjugation and for improved safety profile.[94] In recombinant toxins (e.g., PE40, PE38, or diphtheria toxin DAB486), the cell-binding domains are replaced by single-chain variable fragments (scFv). [94] [165]

Various monoclonal MAb have been conjugated to different toxins for clinical trials:[165] ricin toxin A chain (RTA conjugated to anti-CD7, anti-CD22, and anti-CD25), DT (anti-IL-2R), and PE (anti-CD25, anti-CD22,[166] anti-Lewis Y,[167] and anti-HER-2). A common toxicity is the vascular leak syndrome, characterized by marked fluid overload, dyspnea, and sensorimotor neuropathies.[168]Deglycosylated RTA devoid of mannose and fucose has reduced hepatic sequestration, allowing longer serum half-life. An OR of 31% (2.6% CR, 29% PR) was achieved in patients with NHL following anti-CD22-deglycosylated RTA treatment.[169] Among 16 patients with cladribine-resistant hairy cell leukemia, anti-CD22-dsFv-PE (RFB4[dsFv]-PE38, BL22) induced 11 CR and 2 PR.[170] In addition to transient hypoalbuminemia and elevated aminotransferase levels, 2 patients had serious but reversible hemolytic-uremic syndrome. Other highly toxic natural compounds have also been explored recently, such as calicheamicins[171] and maytansinoids.[172] Gemtuzumab ozogamicin (Mylotarg) is an anti-CD33 antibody that is conjugated to calicheamicin. Acting like a prodrug, calicheamicin is released from the antibody following internalization, forming a diradical that induces double-strand DNA breaks. Gemtuzumab was active in childhood refractory AML[173] and achieved a 30% response rate among refractory AML patients 60 years of age or older.[174] In contrast, antimucin MAb-calicheamicin conjugate has not been successful to date in solid tumors.[175] With most immunotoxins, immunogenicity has been a major constraint, although pegylation may reduce immunogenicity.[176]

Immunoenzymes for ADEPT and Drug-Antibody Conjugates

To enhance the effector functions of MAbs, drugs have been conjugated to MAb for selective tumor delivery. Doxorubicin, melphalan, methotrexate, and vinca alkaloids conjugated to MAb have limited clinical success. BR96-doxorubicin directed at Lewis Y antigen has shown no clinical benefit in phase II trials in breast cancer[177] or gastric cancer.[178] Another novel approach (ADEPT) uses MAb to deliver a covalently conjugated enzyme to the tumor, which can then activate a nontoxic prodrug. [95] [179] Despite preclinical successes, ADEPT has been difficult to translate into clinical benefit. Significant impediments to broaden their clinical implementation include immunogenicity of antibody-enzyme conjugate, as well as the presence of endogenous enzymes or endogenous substrates and endogenous inhibitors of these enzymes within the tumors.


With advances in liposome technology, several liposomal agents have been licensed for use in cancer patients. [180] [181] When coated with polyethylene-glycol, uptake by the reticuloendothelial system is inhibited, thereby prolonging residence time in the blood. Concurrent developments in drug-loading technology have improved the efficiency and stability of drug entrapment in liposomes. Although there is passive accumulation of liposomes in tumors through enhanced permeability and retention, their uptake can be greatly enhanced when engrafted with surface antibodies or their derivatives. For example, scFv or Fab can target liposomes for uptake into tumors bearing CD19,[182] HER-2,[183] EGFR,[184] and GD2.[185] When liposomes fuse with the tumor targets, their contents can be efficiently delivered intracellularly. While their potential is high, the clinical benefit of MAb-targeted liposomes remains to be proven.

Cellular Immunoconjugates with Bisepecific Antibodies

Tumor-selective MAb can be rendered cytophilic by conjugation with MAb that are specific for trigger molecules on T-lymphocytes, NK cells, and granulocytes. [186] [187] [188] These molecules include CD3, CD28, Fc receptors (CD64, CD16), and FcαRI (CD89).[97] One binding site of the bispecific antibody engages CD3 on T-cells; the other binding site determines tumor specificity, for example, β-NHL (CD19),[189] breast cancer (HER-2),[190] and Hodgkin's lymphoma (CD30).[191] Similar successes have been reported for the trigger molecule CD28 for acute lymphoblastic leukemia (CD19 and CD20) [192] [193] and Hodgkin's disease.[194] A phase I trial of the bispecific (HER-2, CD3) and trifunctional (metastatic breast cancer, T cells and FcγRI/III) antibody at low doses (100 mg per injection) was tolerable, tumor responses being noted in 5 of 15 patients.[195] Bispecific MAb targeted at FcγRI can redirect ADCC to specific tumors, including epithelial cancer (EGFR)[196] and breast cancer (HER-2),[197] while those directed at FcγRIII have been successful against Hodgkin's disease (CD30)[198] and breast cancer (HER-2).[197] Because serum IgG competes for FcγR, bispecific MAb that is made to recognize the FcγR outside its Fc-binding domain is also being tested. Although bispecific MAb can induce generalized cytokine release from leukocytes and trafficking of effector cells into tumors is limited,[186] this treatment modality is being actively explored in clinic trials.


Measures have been taken to improve the efficacy of antibody-based cancer therapies.[199] To reduce immunogenicity, MAb have been chimerized and humanized, cloned from phage display libraries,[200]or produced in human IgG-transgenic or human transchromosomal mice ( Fig. 34-2 ). Chimeric MAb are made by joining the antigen-combining variable domains of a mouse MAb to human constant domains: mouse VL to human CL and mouse VH to human CH1-CH2-CH3.[87] In humanized MAb, the antigen-binding loops, known as complementarity-determining regions from a mouse MAb are grafted into a human IgG.[201] Human antibodies can also be derived from scFv or Fab phage display libraries,[202] which are particularly useful for self-antigens.[203] Alternatively, human MAb can be made from hIgG-transgenic mice.[204]


Figure 34-2  Immunogenicity of MAb. CH1, CH2, and CH3, constant region domains of an IgG heavy chain; scFv, single chain variable fragment; VH, variable region of the heavy chain; VL, variable region of the light chain. Red, mouse; blue, human; green, recombinant protein to which scFv is genetically fused.



Because Fc is necessary for antitumor effect, chimerizing mouse MAb with the human IgG1 or IgG3 Fc regions can improve ADCC and CDC functions. Similarly, removing FcγRIIB inhibitory receptor recognition also can enhance antitumor activity.[205] Point mutations in the Fc region have increased its affinity for activation receptors or decrease its affinity for the inhibitory receptor.[206] Glycosylation of IgG at Asn297 stabilizes the tertiary structure of the CH2 domain, which is critical for effector function.[207] Glycosylation depends on the producer line, and increasing the bisected complex oligosaccharides in the Fc region[89] or defucosylation has greatly improved ADCC properties of MAbs.[90] Complement-dependent cytotoxicity can also be improved by Fc region mutations to increase C1q binding.[208]

The antigen-binding affinity, molecular architecture, and oligomerization states of MAb can be reengineered to enhance tumor delivery and therapy.[209] For example, affinity can be increased by using phage display libraries,[210] ribosome display,[211] DNA shuffling,[212] or yeast display combined with DNA shuffling.[213] However, because the binding-site barrier can impede tumor penetration if the MAb has high affinity,[214] the optimal MAb may indeed be a low-affinity IgG binding to a surface antigen that is expressed at high density. In addition, the size of the MAb is critical. ScFv are small (25 kd) and rapidly cleared by the kidney. On the other hand, oligomers with molecular weights in the range of 100 to 200 kd should be ideal for tumor targeting. Besides increasing avidity, oligomerization can increase antitumor activity through a multitude of mechanisms, including CDC/ADCC, induction of apoptosis, growth arrest, and synergy with chemotherapy or immunotoxins.[4] While scFv are a powerful building block for polymeric forms or novel fusion proteins, [215] [216] single-domain antibodies may further expand the possibilities of antibody-based cancer therapies.[217]


Besides the ability to block receptors from interaction with their natural ligand, MAb can inhibit receptor dimerization or receptor interaction with coreceptors.[218] HER-2 is a ligand-less member of the ErbB receptor family that functions as a coreceptor with HER-1/EGFR, HER-3, and HER-4. MAb 2C4 sterically hinders the recruitment of HER-2 into HER ligand complexes and inhibits in vitro and in vivo growth of breast and prostate tumors. The humanized antibody Omnitarg is currently in clinical trial. Most of the MAb targeting effort has been focused on individual tumor cells, but alternative strategies directed at tumor neovasculature,[219] tumor stroma,[220] or tumor infiltrating T cells[221] are promising approaches. Bevacizumab (Avastin), a humanized IgG1 that is specific for vascular endothelial growth factor (VEGF) was effective for metastatic renal cancer [222] [223] and, when combined with chemotherapy, for non-small-cell lung cancer,[224] metastatic CRC,[225] and metastatic breast cancer.[226] Furthermore, MAb can be made to inhibit homing of angiogenic progenitors (e.g., anti-VLA4 [Natalizumab][227] and anti-VEGF-R1[228]) or to block the VEGF-R2/KDR (e.g., IMC-1C11, chimeric anti-KDR). [229] [230] Targeting tumor vasculature may have significant advantages over direct tumor targeting,[231] in that endothelial cells, unlike tumor cells, are less likely to acquire resistance. Another angiogenesis target is aVb3 integrin, which initiates endothelial proliferation, migration, and matrix remodeling.[232] In a phase I trial, chimeric IgG1 (MEDI-522) that is specific for αVβ3[233] was well tolerated, and tumor perfusion was possibly modified. Ipilimumab (also known as MDX-010) is a fully human antibody against human CTLA-4, a molecule on T cells that attenuates their immunocompetence. Ipilimumab is currently being tested in metastatic melanoma as monotherapy or in combination with melanoma-peptide vaccine.[221]


Can One Size Fit All?

Human tumors and their response to MAb-based therapies are heterogeneous. Although MAb share common structures and properties, the successful translation of their antitumor activity into survival benefit in patients requires a much better appreciation of the clinical biology of each individual tumor type as well as an understanding of the fundamental biology of the antigens being targeted.

Is There an Optimal Time to Use MAb Therapy?

It is likely that MAb therapy is most beneficial at the time of minimal residual disease (MRD). Accurate and sensitive measures of MRD will provide objective indicators of tumor response to help guide clinicians to apply this modality more effectively.

What It the Future Role of Antibody Therapy in Treating Cancer?

As a rapidly expanding class of pharmaceuticals, MAb are now an important modality for cancer treatment. They have demonstrated antitumor activity in a broad spectrum of malignancies in the last two decades. The successful integration of MAb and immunoconjugates with other treatment modalities has the potential for achieving further improvements in symptom control and patient survival.


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