Cang et al. Journal of Hematology & Oncology 2012, 5:64
`http://www.jhoonline.org/content/5/1/64
`
`R E V I E W
`Novel CD20 monoclonal antibodies for
`lymphoma therapy
`Shundong Cang1, Nikhil Mukhi2, Kemeng Wang2 and Delong Liu2*
`
`JOURNAL OF HEMATOLOGY
`& ONCOLOGY
`
`Open Access
`
`Abstract
`
`Rituximab (RTX), a monoclonal antibody (mAb) against CD20, has been widely used for lymphoma therapy. RTX in
`combination with cyclophosphamide /doxorubicin /vincristine /prednisone (R-CHOP) remains the standard frontline
`regimen for diffuse large B-cell lymphoma. However, suboptimal response and /or resistance to rituximab have
`remained a challenge in the therapy of B-cell non-Hodgkin’s lymphoma (NHL). Novel agents are under active
`clinical trials. This review will summarize the latest development in new mAbs against CD20, which include
`second-generation mAbs, ofatumumab, veltuzumab (IMMU-106), ocrelizumab (PRO70769), and third-generation
`mAbs, AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutumumab).
`
`Background
`(mAb)
`antibody
`a monoclonal
`Rituximab (RTX),
`against CD20, has been widely used for lymphoma
`therapy [1-4]. RTX in combination with cyclophospha-
`mide /doxorubicin /vincristine /prednisone (R-CHOP)
`remains the standard frontline regimen for diffuse large
`B-cell
`lymphoma (DLBCL) [5,6]. However, suboptimal
`response and /or resistance to rituximab have remained a
`challenge in the therapy of B-cell non-Hodgkin’s lymph-
`oma (NHL). Novel agents are under active clinical trials.
`This review will summarize the latest development in
`new mAbs against CD20.
`
`Rituximab, the first-generation CD20
`monoclonal antibody
`CD20 is the first B-cell specific antigen defined by the
`monoclonal antibody tositumomab [7,8]. Human CD20
`is encoded by the gene MS4A1 gene located on chromo-
`some 11q12.2 [9]. CD20 molecule is a 297 amino acid
`phosphoprotein with four
`transmembrane domains
`(Figure 1). It plays a critical role in B-cell development.
`CD20 has been a superb biomarker for immunotherapies
`targeting B-cell derived diseases [10]. It is known to
`function through binding to Src family tyrosine kinases,
`such as Lyn, Fyn, and Lck, and believed to be involved
`as a result in phosphorylation cascade of intracellular
`
`* Correspondence: delong_liu@nymc.edu
`2Department of Medicine, New York Medical College and Westchester
`Medical Center, Valhalla, NY 10595, USA
`Full list of author information is available at the end of the article
`
`proteins. It is a tetra-transmembrane protein that essen-
`tially remains on the membrane of B cells without dis-
`sociation or
`internalization upon antibody binding
`(Figure 2) [11]. RTX, the first generation CD20 mAb,
`can induce complement-dependent cytotoxicity (CDC)
`and antibody-dependent cellular cytotoxicity (ADCC),
`leading to its clinical activity against lymphoma cells
`[12]. CDC represents the primary mechanism for cell-
`killing by RTX. However, some lymphoid cells ( i.e. 10%
`of CLL cells) were resistant to CDC because of lower
`levels of complement activation or decreased cytotox-
`icity of activated complements. In addition, RTX can
`lead to apoptosis of B cells upon binding to CD20 and
`therefore can directly inhibit cell growth [13]. Recently,
`a novel mechanism of cell killing by mAbs was reported
`to involve reactive oxygen species mediated through
`NADPH [14].
`RTX has been widely used for lymphoma therapy
`[1-4,15-17]. R-CHOP chemotherapy remains the stand-
`ard regimen for newly diagnosed DLBCL [3,5,18].
`CD20 mAbs conjugated to nuclear isotopes have also
`been approved for lymphoma therapy [18-22]. RTX
`has also been studied in new combination regimens,
`particularly for
`relapsed and refractory lymphomas
`[23-31].
`To increase antitumor activity and Fc binding affinity
`for the low-affinity FcγRIIIa receptor (CD16) on immune
`effector cells, new generations of anti-CD20 monoclonal
`antibodies (mAbs) are being developed [7,8,11].
`
`© 2012 Cang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
`Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
`reproduction in any medium, provided the original work is properly cited.
`
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`
`Figure 1 The structure of CD20 molecule. Human CD20 is encoded by the gene MS4A1 gene located on chromosome 11q12.2. CD20
`molecule is a 297 amino acid phosphoprotein with four transmembrane domains.
`
`Second-generation anti-CD20 mAbs
`The second-generation anti-CD20 mAbs include ofatu-
`mumab, veltuzumab, and ocrelizumab. These are huma-
`nized to reduce immunogenicity.
`Ofatumumab (OFA) is a fully human type I anti-CD20
`IgG1kappa mAb [15,32-37]. Ofatumumab binds to both
`the small and large extracellular loops (ECL) of CD20
`molecule, and is more effective than rituximab at killing
`target cells. It has been shown to be more potent than
`RTX against both RTX- sensitive and resistant cells [38].
`Its activity against RTX-resistant cells and the potent
`CDC effect are believed to be due to the proximal epi-
`tope of the small loop of CD20 molecule and the high
`capacity for C1q activation.
`
`OFA (arzerra) has been approved for treatment of
`relapsed or refractory CLL who have failed fludarabine
`and alemtuzumab (FA-ref )
`[39]. OFA is given IV
`weekly on a fixed dose, 300 mg for dose 1, and 2000 mg
`weekly x 7 in subsequent doses. This is followed by
`every four weeks for 4 more doses [36]. In FA-ref CLL
`patients, the response rate was 58%. OFA was also stud-
`ied in 116 patients with RTX-refractory follicular lymph-
`oma (FL)
`[40]. These patients
`received 8 weekly
`infusions (dose 1, 300 mg and doses 2–8, 500 or 1000
`mg). The median age was 61 years, and the median
`number of prior therapies was 4. The overall response
`rate (ORR) was 13% and 10% for the 500-mg and 1000-
`mg arms, respectively (Table 1). The median PFS was
`
`Figure 2 The molecular configuration of CD20 molecule. CD20 is a tetra-transmembrane protein that essentially remains on the membrane
`of B cells without dissociation or internalization upon antibody binding. The binding sites of CD20 monoclonal antibodies, rituximab and
`ofatumumab, are indicated.
`
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`Cang et al. Journal of Hematology & Oncology 2012, 5:64
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`
`Table 1 Second generation CD20 monoclonal antibodies
`Monoclonal Ab Ig type
`Patients Regimen
`
`Ofatumumab
`(OFA)
`
`IgG1 Kappa
`
`116
`
`Ofatumumab (Refractory FL)
`500 mg 1000mg
`
`Overall response
`rate(%)
`13% 10%
`
`Adverse events
`
`Reference
`
`Infections, rash, urticaria, pruritis,
`neutropenia, anemia,
`thrombocytopenia
`
`[40]
`
`[41]
`
`[35]
`
`[42]
`
`[43]
`
`Veltuzumab
`
`IgG1
`
`Ocrelizumab
`
`IgG1
`
`59
`
`61
`
`82
`
`47
`
`O-CHOP (untreated FL)
`500 mg 1000 mg
`
`90% 100%
`
`Leucopenia, neutropenia
`
`O-FC (Frontline therapy for CLL)
`500 mg 1000 mg
`
`77% 73%
`
`Neutropenia, thrombocytopenia,
`anemia, infection
`
`Veltuzumab (Relapsed/refractory B
`cell NHL) 80 to 750 mg/m2
`
`44%(FL) 83%
`(MZL) 43%(DLBL)
`
`Fatigue, pruritis, asthenia, fever,
`dyspnea, headache, infection
`
`Ocelizumab (Relapsed/Refractory FL)
`750mg/m2
`
`38%
`
`Infusion related reaction,
`nasopharyngitis, asthenia,
`lymphopenia, infection
`
`Abbreviations: DLBCL: diffuse large B cell lymphoma; FL: follicular lymphoma; MZL: marginal zone lymphoma; NHL: non-Hodgkin lymphoma.
`
`5.8 months. Infections, rash, urticaria, fatigue, and prur-
`itus were the most common adverse events. Severe ad-
`verse
`events
`included neutropenia,
`anemia,
`and
`thrombocytopenia in a subset of patients.
`OFA is being explored in combination with other
`agents in various B-cell neoplasms. An international,
`phase II trial was conducted to assess two doses of
`ofatumumab combined with CHOP (O-CHOP)
`for
`frontline treatment for follicular lymphoma [41]. The
`study randomized 59 patients to receive either OFA
`500 mg (n = 29) or 1000 mg (n = 30) on day 1, with
`CHOP on day 3 every 3 weeks for six cycles. ORR
`was 90% for the 500-mg group and 100% for the
`1000-mg group (Table 1). CR/CRu was 62%. The
`most common severe adverse events were leucopenia
`(29%) and neutropenia (22%). O-CHOP was reported
`to be safe and effective as frontline therapy for FL
`patients.
`Another international randomized phase II trial was
`done using OFA in combination with fludarabine 25
`mg/m2 and cyclophosphamide 250 mg/m2 on days 2–4
`in course 1 and on days 1–3 for courses 2–6 [35]. This
`was repeated every 4 weeks for 6 courses. Two OFA
`dose levels, 500 mg (n = 31) or 1000 mg (n = 30), were
`given
`to
`patients with
`untreated CLL
`after
`randomization. The first OFA dose was 300 mg for both
`cohorts. The median age of the study pts was 56 years;
`17p deletion was seen in 13% of patients. CR rate was
`32% for the 500-mg and 50% for the 1000-mg cohort.
`ORR was 77% and 73%, respectively. Beta2-microglobulin
`and the number of O-FC courses given correlated sig-
`nificantly with CR, ORR, PFS, according to univariate
`analyses (P < .05). Neutropenia (48%), thrombocytopenia
`(15%), anemia (13%), and infection (8%) were found
`to be the most common severe adverse events. The
`study concluded that O-FC is active and safe in
`treatment-naive CLL patients,
`including
`high-risk
`patients with 17p deletion.
`
`Veltuzumab (IMMU-106, hA20) has more potent
`binding avidities and a stronger effect on CDC than
`rituximab [44]. Veltuzumab is a humanized, type I anti-
`CD20 IgG1 mAb,
`engineered recombinantly with
`complementarity-determining regions (CDRs) identical
`to rituximab, except for a single amino acid change,
`Asp101 instead of Asn101, in the CDR3 of the variable
`heavy chain [10,44]. This modification results in signifi-
`cantly slower off-rates and increased CDC cytotoxicity
`in three human lymphoma cell lines. Clinically, veltuzu-
`mab has been studied in over 150 patients with lymph-
`omas and autoimmune diseases.
`In a multicenter
`phase I/II dose-finding study of veltuzumab in relapsed/
`refractory B-cell non-Hodgkin's
`lymphoma
`(NHL),
`eighty-two patients (median age, 64 years; 79% stage III/
`IV, one to nine prior treatments) received infusions of
`80–750 mg/m2 once-weekly for four doses, with no
`grade 3 to 4 drug-related adverse events other than
`infusion-related reactions [42]. Complete response (CR)
`was seen in 27% of FL patients despite failure of two to
`five prior rituximab-containing regimens. ORR for FL,
`MZL, and DLBCL was 44%, 83%, and 43%, respectively
`(table 1). The median duration of responses was 19.7
`months. B cell depletion was seen at all dose levels stud-
`ied. The depletion occurred after the first infusion. The
`veltuzumab serum half-lives were similar after the fourth
`infusion, and mean antibody serum levels were higher
`than the values generally considered important for anti-
`CD20 therapy (i.e., 25 mg/ml). Subcutaneous injections
`of low doses (80–320 mg) were also studied and have
`also proved to be safe and pharmacologically active [45].
`Ocrelizumab (PRO70769) is another type I second
`generation humanized mAb that differs from rituximab
`at several amino acid positions within the CDRs of the
`light chain and heavy chain variable regions. With
`enhanced efficacy toward lymphoid malignancies and
`increased binding affinity for the low-affinity variants of
`the FcγRIIIa receptor (CD16), this mAb has increased
`
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`
`ADCC and lower CDC activity compared with rituxi-
`mab. This mAb has been evaluated in a phase I/II
`study for safety and efficacy in patients with relapsed/
`refractory follicular lymphoma (FL) after failing prior
`RTX therapy [43]. Forty-seven patients were enrolled in
`three dose cohorts and received eight infusions every
`3 weeks: cohort A, 200 mg/ m2 (n = 15); cohort B,
`375 mg/ m2 (n = 16); cohort C, first dose 375 mg/ m2
`with seven subsequent doses at 750 mg/ m2 (n = 16).
`The patients had a median age of 58 years and had
`received a median of 2 (range 1–6) prior regimens. The
`grade 3/4 toxicity occurred in 9% of patients. The most
`common toxicity was infusion-related reactions which
`occurred in 74% of the patients. The ORR was 38% re-
`gardless of affinity variants in the FcγRIIIa. The median
`follow-up was approximately 28 months, and the median
`PFS was 11.4 months.
`
`Third-generation anti-CD20 mAbs
`The third-generation humanized CD-20 mAbs have an
`engineered Fc region to increase their binding affinity
`for the FcγRIIIa receptor. Three third-generation mAbs,
`AME-133v, PRO131921 and GA101, are undergoing ac-
`tive clinical development.
`AME-133v (LY2469298, ocaratuzumab) is a type I,
`humanized IgG1 mAb. Its binding affinity to CD20 has a
`13 to 20- fold increase with 5 to 7- fold higher avidity to
`the low-affinity (F/F and F/V) variants of FcγRIIIa recep-
`tor. These may have been the mechanisms to overcome
`the lower
`response rates and shorter duration of
`responses to rituximab. A phase I study was done with
`dose escalation in 10 Japanese patients with relapsed and
`/or refractory FL. It was administered by intravenous in-
`fusion at 100 or 375 mg/m2 weekly for 4 weeks. Nine
`patients were F-carriers while one was homozygous
`for valine (V/V) at position 158 of FcγRIIIa. There
`were no dose-limiting toxicities. Five (50%) of
`ten
`patients responded to ocaratuzumab treatment (three
`CR, one unconfirmed CR and one partial response).
`
`Ocaratuzumab was well tolerated and clinical activity
`was observed in FL patients pretreated with rituximab,
`mostly consisting of F-carriers [46]. Another phase I
`dose escalation study from US has also been reported in
`23 relapsed FL patients. The dosages were well tolerated
`from 2 up to 375 mg/m2 [47]. This highest dose was
`used in a phase II trial in 44 patients with relapsed FL
`following prior rituximab[48]. These patients with the
`low-affinity FcγRIIIa polymorphism (F-carriers) received
`375 mg/m2 of ocaratuzumab weekly for 4 doses. The
`ORR was 36% and median progression free survival
`(PFS) reached 91 weeks (Table 2). In this analysis, there
`were 56 patients who received 100 and 375 mg/m2 of
`ocaratuzumab. Eight of these patients had a median of 2
`prior rituximab treatments (range 1–6). Five of the 8
`patients showed a longer PFS after ocaratuzumab ad-
`ministration, compared with last rituximab treatment.
`These 5 patients had the F/F low-affinity genotype of
`FcγRIIIa. Three of the patients had prolonged remission
`[48]. Ocaratuzumab will need to be compared to rituxi-
`mab in randomized clinical trials to substantiate its po-
`tential clinical advantages.
`PRO131921 is another humanized anti-CD20 mAb
`recombinantly
`engineered for
`enhanced CDC and
`ADCC activities over RTX [15,52,53].
`In preclinical
`in vivo studies, it was shown to have better anti-tumor
`efficacy than rituximab. PRO131921 was given to
`patients (pts) with relapsed and /or refractory indolent
`lymphoma who failed rituximab-containing regimen
`[51]. This phase I study determined the maximum toler-
`ated dose (MTD) and the pharmacokinetics
`(PK).
`PRO131921 was infused weekly for 4 weeks on days 1, 8,
`15 and 22. The dose of the first infusion was half of sub-
`sequent infusions. Twenty-four pts were treated with
`PRO131921 at doses escalated from 25 mg/m2 to 800
`mg/m2. A median of 2 (range 1-6) prior regimens were
`found in these pts. PRO131921 had no MTD in this
`study. The most common adverse events were infusion-
`related reactions,
`limited mostly to the first infusion.
`
`Table 2 Third Generation CD20 monoclonal antibodies
`Monoclonal Ab Ig type Patients Regimen
`
`Obinutuzumab
`(GA-101)
`
`IgG1
`
`21
`
`Obinutuzumab (Refractory B cell
`NHL) 1600/800 mg 400/400 mg
`
`Overall response
`rate
`60% 35%
`
`28
`
`28
`
`24
`
`56
`
`G-CHOP (Relapsed or refractory FL)
`1600/800 mg 400/400 mg
`
`G-FC (Relapsed or refractory FL)
`1600/800 mg 400/400 mg
`
`PRO131921 (Relapsed/refractory B
`cell NHL) 25 to 800 mg/m2
`
`Ocaratuzumab (Relapsed/Refractory
`FL) 100 mg/m2 375mg/m2
`
`94%
`
`93%
`
`27%
`
`36%
`
`PRO131921
`
`IgG1
`
`Ocaratuzumab
`(AME-133v)
`
`IgG1
`
`Adverse events
`
`Reference
`
`Infusion related reaction, neutropenia,
`anemia, thrombocytopenia, tumor lysis
`syndrome
`
`Infusion related reaction, neutropenia,
`neuropathy, infection
`
`Infusion related reaction, neutropenia,
`rash, infection
`
`Infusion related reaction, upper
`respiratory tract infection, neutropenia
`
`Infusion related reaction, nasopharyngitis,
`asthenia, lymphopenia, infection
`
`[49]
`
`[50]
`
`[50]
`
`[51]
`
`[48]
`
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`
`Dose limiting toxicity (DLT) included a significant infu-
`sion reaction and grade 3 joint pain and fatigue after 2
`infusions. There was a correlation between drug expos-
`ure and tumor shrinkage (p=0.049) as well as clinical
`response (p=0.034). This suggested that drug clearance
`(e.g. by tumor in excess of drug) is proportional to
`clinical efficacy. Twenty two of the 24 pts were evaluable
`at the time of report in 2009. There were 6 partial re-
`sponse (PR 27%), 13 stable disease (SD), and 3 disease
`progression (PD). Half of 10 pts in the two highest dose
`cohorts responded. Further clinical trials are underway.
`GA101 (RO5072759, obinutuzumab) is a fully huma-
`nized, type II, IgG1 mAb derived from humanization of
`the parental B-Ly1 mouse antibody and subsequent gly-
`coengineering of Fc region [54-57]. GA101 binds CD20
`through a totally different orientation than rituximab
`and over a larger epitope. It appears to have more potent
`activity through direct killing as well as NK-cell
`mediated ADCC effect. GA101 was shown to have activ-
`ity in RTX-resistant cell lines [58,59].
`In an open label multicenter, phase I/II study, GA101
`was evaluated in patients with relapsed /refractory CD20
`+ NHL/CLL[60]. In the non-randomized dose-escalating
`phase I (3 + 3 design), 21 patients were treated with
`GA101 (50–2,000 mg) on days 1 and 8 of cycle 1, and
`day 1 in cycles 2–8 (21-day cycles). ORR was 56%
`(CR=31%, PR=25%). In the phase II part of the study,
`patients with indolent NHL were randomized to one of
`two doses: 1,600/800 mg (n = 22, ORR 60%), or 400/400
`mg (n = 18, ORR 35%). The median follow-up time was
`23.1 months. The median PFS for patients with FL was
`11.8 months for the high-dose cohort, and 6.0 months
`for the low dose cohort (HR: 0.77 [95% CI 0.34–1.77).
`The most common adverse events (AE) were infusion-
`related reactions (400/400 mg: 72%; 1,600/800 mg: 73%).
`Responses were also seen among the 5 patients who
`were retreated with GA101. PK data from the studies
`have suggested that
`responding patients metabolize
`GA101 more slowly than non-responders [61].
`Obinutuzumab (GA101) in combination with cyclo-
`phosphamide /doxorubicin /vincristine /prednisone (G-
`CHOP) or fludarabine /cyclophosphamide (G-FC) has
`been studied in patients with CD20+ relapsed/refractory
`FL in an open-label, multicenter, randomized Phase Ib
`study (BO21000). Response rates were 94% for G-CHOP
`and 93% for G-FC. Serum levels of GA101 from these
`pts receiving combination chemotherapies were mea-
`sured by ELISA. GA101 PK data were reported [50]. The
`serum concentrations of GA101 corresponded to the
`GA101 dose level that pts received, regardless of chemo-
`therapy arm.
`GA101 represents the first third-generation type II gly-
`coengineered CD20 mAb which entered randomized
`phase II/III clinical trials. GA101 was compared to RTX
`
`in a randomized phase II study in CLL/NHL patients
`[62]. In this study, a total of 175 pts (149 FL) were ran-
`domized to receive 4 weekly infusions of either GA101
`(1000 mg, n=87) or rituximab (375 mg/m2, n=88). Main-
`tenance treatment with GA101 or rituximab every 2
`months for up to 2 years at the same dose was given to
`responders. ORR was the primary endpoint in the FL
`population. In this population, ORR for GA101 was 43.2
`(32/74) v 38.7 (29/75) for rituximab. The CR/CRu rate
`was 10.8 in the GA101 arm v 6.7 for rituximab. There-
`fore, this first head to head trial of GA101 against RTX
`demonstrated higher ORR and similar adverse events.
`Phase III trials of GA101 in combination with chemo-
`therapy are ongoing.
`
`Conclusions and future directions
`Although RTX and newer mAbs against CD20 have
`revolutionized lymphoma therapy, a significant popula-
`tion of patients still succumbs to lymphomas. Novel
`agents with different mechanism of actions are being
`explored [63-76]. Bortezomib is an active agent for re-
`fractory mantle cell and other lymphomas [77-85]. Lena-
`lidomide,
`an immunomodulatory
`agent, has been
`studied for lymphoma therapy [67,86]. mTOR inhibitors,
`everolimus and temsirolimus, are being studied for treat-
`ment of refractory and relapsed lymphomas [87-94].
`New biomarkers, such as microRNAs, STATs and Tregs,
`appear to be useful for assisting lymphoma diagnosis and
`for developing new therapeutic agents [65,74,75,95-97].
`Novel antibodies directed against
`lymphocyte-specific
`antigens, such as CD19 [98-101], CD22 [102-112], and
`CD30 [113-116], have shown promises for clinical appli-
`cations. Combination regimens among these novel
`agents may provide further improvement on the outcome
`of lymphoma therapy.
`
`Competing interest
`The authors have no relevant conflicts of interest.
`
`Authors’ contributions
`All authors have contributed to data preparation, drafting and revising the
`manuscripts. All authors have read and approved the final manuscript.
`
`Author details
`1Department of Oncology, People’s Hospital, Henan Province, China.
`2Department of Medicine, New York Medical College and Westchester
`Medical Center, Valhalla, NY 10595, USA.
`
`Received: 26 September 2012 Accepted: 9 October 2012
`Published: 11 October 2012
`
`2.
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