An update on newer monoclonal antibodies in lymphoma therapy

Subhashini Archana Kadavakolan; Sonam Puri; Sandeep Sahay; Jitesh Joshi

doi:10.4103/2454-6798.180581

View/Download PDF

Buy Reprints

PDF

Translate this page into:

Review Article

02 (

); 003-007

doi:

10.4103/2454-6798.180581

An update on newer monoclonal antibodies in lymphoma therapy

Subhashini Archana Kadavakolan, Sonam Puri¹, Sandeep Sahay^2,, Jitesh Joshi³

Department of Internal Medicine, Sir Seewoosagur Ramgoolam Medical College, University of Mauritius, Mauritius

Department of Internal Medicine, University of Connecticut, CT, USA

Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Department of Internal Medicine, Arkansas Cancer Institute, Little Rock, AR, USA

Address for correspondence: Dr. Sandeep Sahay, Department of Internal Medicine, Baylor College of Medicine, 6620 Main St, 11B.12, Houston, TX, USA. sandeep.sahay@bcm.edu

Licence

Disclaimer:
This article was originally published by Thieme Medical and Scientific Publishers Private Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

In 2014, an estimated 9.4% of all new cancers in the US were accounted to hematological cancers. Most of these cancers have a B-cell origin and on the cell surface express antigen CD20-known to restrict B-cells. Considering the intrinsic immune status of the patients receiving chemotherapy, monoclonal antibodies (mAbs) are designed to provide active or passive immunotherapy. Clinical success of rituximab-anti-CD20 mAb in the treatment of lymphoma has led to the development of newer generations of mAb to increase the anti-tumor activity. Hence, recent advances in lymphoma therapy are being built on the conventional prototype of anti-CD20 mAb-rituximab. Our review is an update on the advances in lymphoma therapy using mAb against CD20 including the second generation-ofatumumab, veltuzumab, ocrelizumab, and the third-generation mAbs-ocaratuzumab and obinutuzumab.

Keywords

CD20 monoclonal antibody

lymphoma therapy

recent advances

Show Related Articles from PubMed

Introduction

Various monoclonal antibodies (mAbs) target different epitopes namely as CD19, CD20, CD22, CD40, CD52, and CCR4 that are present on the lymphoma surface.¹ Encoded by the gene MS4A1 gene located on the chromosome 11q12.2, CD20 molecule is a 297 amino acid phosphoprotein with four transmembrane domains.² It plays a crucial role in B-cell development and has been a reliable biomarker for immunotherapies targeting B-cell derived diseases.³ The malignant cells have known to surpass the initial immune-surveillance and gradually develop resistance to medications through polymorphism of the target Fc receptors.

After its approval in 1997, rituximab a mAb against CD20 is being effectively used for the follicular lymphoma (FL) – B-cell cancer. Consequently, many studies conducted showed significant improvement upon addition of rituximab to initial chemotherapeutic regimens for non-Hodgkin's lymphoma (NHL) namely-diffuse large B-cell lymphoma and FL.^4,5,6,7,8,9 Since this success with rituximab, newer, and enhanced mAbs were developed to be used in place of rituximab or in diseases refractory to it. The gradual expansion of mAbs to unblock the immune checkpoints by targeting program death ligand-1 as well as the concept of bispecific T cell engagers has opened newer options in lymphoma chemotherapy. Few of the novel mAb are being used in the present clinical practice or have the potential to revolutionize lymphoma treatment options in the future Table 1.

Table 1 Anti-CD20 monoclonal antibodies currently approved or being investigated in clinical trials for B-cell lymphomas

mAb	Type of CD20 antibody*	Generation**	Structure	Mechanism of action (ADCC/CDC/PCD)	Comparison to rituximab	References
Rituximab	I	1	IgG1 human mouse chimeric	++/++/+	-	⁷
Ofatumumab	I	I1	Fully human IgG1	+++/++++/++	Superior CDC, decreased PCD	¹⁹
Veltuzumab	I	II	Humanized IgG1	++/++/+	Longer “off-rate,” more avid CD20 binding can be given subcutaneously	²¹
Ocrelizumab	I	II	Humanized fusion IgG1	+++/+/+	Enhanced binding to FCγRIIa	²²
Obinutuzumab (GA101)	II	III	Murine bly-l derived humanized IgG1	++++/−/++++	Superior PCD/ADCC; no CDC	²³
BM-ca	I/II		Humanized IgG	++++/+++/++++	Different epitope, superior ACDD, CDC and PCD	^34,35,36
Alemtuzumab	NA (target CD52)		Humanized IgG1	++++/+++/+++	Anti CD52, increased toxicities	^30,31

*Type of mAb - compared to a Type I mAb, a Type II mAb does not evoke a complement response, however, may have increased PCD/ADCC, **Generations of mAB - First generation - originally approved mAB against a clinically validated target, Second generation - follow-up antibodies with improved variable domains that target the same epitopes with higher or lower affinity, or have different antibody formats, e.g., pegylation and Fc-fusion proteins, Third generation - target different epitopes or trigger other mechanisms of action. ADCC - Antibody dependent cellular cytotoxicity; CDC - Complement dependent cytotoxicity; CLL - Chronic lymphocytic leukemia; mAB - Monoclonal antibody; PCD - Programmed cell death; NA - Not available; ++++ /+++/++/+ - It is the relative strength of the antibody towards the mechanism of action in comparison to rituximab

First-generation CD20 Monoclonal Antibody

Rituximab

It is a first generation chimeric mAb targeting CD20 on the B-cell surface. Even though the primary mechanism of cell-killing for rituximab is complement dependent cytotoxicity (CDC), it can also induce antibody-dependent cell mediated cytotoxicity (ADCC) and direct cellular effects that eventually leads to apoptosis of lymphoma cells.¹⁰ It has boosted the response rates and progress-free survival in first-line as well as refractory cases and significantly improved the overall survival in lymphoma patients.^7,11,12 Various studies conducted showed that approximately 60% of previously untreated lymphoma patients and 40–50% of those with refractory/relapsed disease respond to rituximab monotherapy.¹³ Remission periods with maintenance therapy are significantly prolonged in patients with FL.^4,5

There are some lymphoid cells (about 10%) that are resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complements.¹⁴ Hence, novel methods were developed to increase the antitumor activity and Fc binding for the low – affinity FcγRIIIa receptor (CD 16) on immune effector cells.¹⁵

Second-generation CD20 Monoclonal Antibody

Ofatumumab (HuMax-CD20; Arzerra)

It is a human Type I anti-CD20 IgG1 kappa mAb that binds loop domains of the antigen at an epitope different from that of rituximab.^14,16 It is Food and Drug Administration-approved, as combination chemotherapy for treatment of chronic lymphocytic leukemia (CLL) in patients with contraindication to fludarabine therapy or resistance to fludarabine and/or alemtuzumab therapy.¹⁷ Furthermore, the combination of ofatumumab with pentostatin and cyclophosphamide had better treatment outcomes compared to the older fludarabine, cyclophosphamide and rituximab regimen.¹⁸ An international phase-II trial contrasted the present chemoimmunotherapy regimen (CHOP) with combined treatment with ofatumumab (O-CHOP) for FL therapy.¹⁹ In 59-patients tested, it had an overall response rate (ORR) of 90–100% with significant clinical improvement in treatment outcomes. Common adverse effects encountered with ofatumumab include infections, rash, urticaria, pruritis, neutropenia, anemia, and thrombocytopenia.¹⁹

Veltuzumab (IMMU-106, hA20)

It is Ig1 humanized mAb structurally different from rituximab by only one amino acid targeting the CD20 with therapeutic effects greater than that of rituximab mainly due to its higher CDC and longer retention on the cellular surfaces.²⁰ This conclusion was drawn through extensive Phase I/II studies carried out using veltuzumab on patients with FL, who were initially treated with rituximab. In these 82 patients with relapsed/refractory B-cell NHL, veltuzumab infusions were well-tolerated with only infusion-reactions.²¹

Ocrelizumab (PRO70769)

It is a Type I second generation anti CD20-mAb derived with a different prototype of human Fc that binds firmly to low affinity variants of FcγRIIIa receptor (CD16). It uses a separate complement determining region from that of rituximab with an increased ADCC and lower CDC activity. To oversee the safety profiles of ocrelizumab, a brief study with relapsed/refractory cases of Follicular lymphoma (FLL) on monotherapy were analyzed. This showed results comparable to that of rituximab monotherapy with an ORR of 38%.²² Adverse effects include infusion reaction, nasopharyngitis, asthenia, lymphopenia, and infections.²²

Third-generation Monoclonal Antibody

The three third generation humanized CD20 mAbs are AME-133 v, PRO131921, and GA101 that have been engineered Fc region to increase their binding affinity for the FcγRIIIa receptor.

Obinutuzumab (GA101)

It is the first, third-generation Type II glycoengineered CD20 mAb to have gone into Phase II/III randomized clinical trial. The aim was to compare its safety and efficacy with rituximab in relapsed indolent lymphomas.²³ Obinutuzumab has an enhanced direct cell death via a nonapoptotic, caspase-independent mechanism that is independent to Fcγ-receptors. In patients with Fc-dependent tumor mechanisms or tumor resistance to induction, chemotherapy obinutuzumab may be effective.¹ Sehn et al. carried this study in 175 patients and found that obinutuzumab had a higher ORR than rituximab (44.6% vs. 33.3%). However, this difference was not converted into improved progression-free survival (PFS).²³

Ocaratuzumab

Previously referred to as LY2469298 or AME-133 v, Ocaratuzumab is a humanized IgG1 Fc-engineered mAb against CD20 with pharmacokinetics similar to rituximab.²⁴ FcγRIIIa (CD16) genotyped patients can have a single-gene polymorphism (SNP) on immune mediator cells namely NK cells and macrophages and can activate ADCC and a higher affinity to its ligand (CD20) than rituximab.²⁴ Since 80% of patients with diagnosed FL are FcγRIIIa F-carrier, an opportunity exists to improve the interaction between CD16 and CD20.²⁴

Studies conducted by Cartron et al., Weng and Levy and Swiss Clinical Cancer Research showed that rituximab monotherapy is effective in patients with FL and less-effective in F-carriers.^25,26,27 Bowles et al.,³⁷ conducted preclinical studies in vitro showed CD20 enhancing ADCC is more effective than rituximab in activating NK cells. Relapsed FL patients with FcγRIIIa variant treated with rituximab previously, upon receiving treatment with AME-133 v were to found to have an ORR of 50%, according to Tobinai et al.²⁸ In the Phase I trial conducted, ocaratuzumab was safe and well-tolerated in the tested dose range.²⁴ The most common adverse effects seen in Phase I study were an infusion related reaction, nasopharyngitis, asthenia, lymphopenia, and infection.¹⁴

PRO131921

A recombinant humanized anti-CD20 mAb that has through various preclinical studies has shown to have greater CDC and ADCC activity than rituximab.¹⁶ Casulo et al. carried out a Phase I study to determine the maximum-tolerated dose and the pharmacokinetics of PRO131921.²⁹ Infusion reactions, joint pain, and fatigue were significant in few of these patients and led to dose-limiting toxicity.²⁹

Others

Alemtuzumab

Alemtuzumab (Campath^®) is a recombinant mAb against CD 52-a cell-surface protein found on most of the normal and malignant B and T lymphocytes. It is a DNA-derived humanized IgG1 kappa mAb with a significant use in patients with genetically high-risk treatment-resistant CLL.³⁰ The subgroups that were hypothesized to benefit the most included patients with 17p deletion, bone marrow infiltration and refractory autoimmune cytopenia.^30,31 It received approval in the US for the first time in 2001 and was essentially reserved for patients with CLL who had received fludarabine therapy yet had progressive disease.^30,32 In 2007, it demonstrated an improved PFS over single agent chlorambucil as the first line treatment and received complete approval.^32,33

The high incidence of Grade 3/4 adverse events including neutropenia (up to 64%) and infusion reactions (up to 35%) has limited the use of alemtuzumab.³³ Studies are being conducted to improve the safety profile of the drug by reducing the dose without affecting its anti-tumor property.³¹ In addition, alemtuzumab has been found to be ineffective when used as a single agent, particularly in nodal disease. Hence, combination chemotherapy with other antibodies or with steroids is more effective and less toxic. mAb namely rituximab and steroids – glucocorticoids have been more potent and act in a TP53-independent fashion.³⁰ Subcutaneous injection has also shown to reduce its serious adverse effects further.³⁰

BM-ca

A novel humanized anti-CD20 antibody similar to ofatumumab with regards to its potent effect against rituximab-sensitive SU-DHL-4 cells and rituximab-resistant RC-K8 cells.³⁴ BM-ca binds to a unique epitope and possesses properties of both Type I and II antibodies. Kobayashi et al., study showed that ADCC and anti-proliferative effect of BM-ca was more potent than other anti-CD20 mAb.³⁴ Vega et al. conducted a study and hypothesized that BM-ca may be superior to rituximab in inhibiting the pathways (NF-kB and p38 MAPK) and are partly responsible for cell growth and response to cytotoxic therapy.³⁵ This is accounted to the fact that BM-ca binds to a different epitope than rituximab or ofatumumab that results in its higher affinity and exhibits different molecular signaling.³⁶ To further know about the complete potential of BM-ca, ongoing clinical trials are being conducted to test its therapeutic activity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

Illidge T, Cheadle E J, Donaghy C, Honeychurch J. Update on obinutuzumab in the treatment of B-cell malignancies. Expert Opin Biol Ther. 2014;14:1507-17.
[Google Scholar]
Tedder T F, Engel P. CD20: A regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15:450-4.
[Google Scholar]
Goldenberg D M, Morschhauser F, Wegener W A. Veltuzumab (humanized anti-CD20 monoclonal antibody): Characterization, current clinical results, and future prospects. Leuk Lymphoma. 2010;51:747-55.
[Google Scholar]
Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi J F. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: Results of the GELA-GOELAMS FL2000 study. Blood. 2008;112:4824-31.
[Google Scholar]
van Oers M H, Van Glabbeke M, Giurgea L, Klasa R, Marcus R E, Wolf M. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28:2853-8.
[Google Scholar]
Marcus R, Imrie K, Solal-Celigny P, Catalano J V, Dmoszynska A, Raposo J C. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579-86.
[Google Scholar]
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-32.
[Google Scholar]
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-42.
[Google Scholar]
Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12:1013-22.
[Google Scholar]
Robak T, Robak E. New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies. BioDrugs. 2011;25:13-25.
[Google Scholar]
Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004;104:3064-71.
[Google Scholar]
Schulz H, Bohlius J F, Trelle S, Skoetz N, Reiser M, Kober T. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst. 2007;99:706-14.
[Google Scholar]
Hainsworth J D, Litchy S, Barton J H, Houston G A, Hermann R C, Bradof J E. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-51.
[Google Scholar]
Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012;5:64.
[Google Scholar]
Alduaij W, Illidge T M. The future of anti-CD20 monoclonal antibodies: Are we making progress? Blood. 2011;117:2993-3001.
[Google Scholar]
Czuczman M S, Gregory S A. The future of CD20 monoclonal antibody therapy in B-cell malignancies. Leuk Lymphoma. 2010;51:983-94.
[Google Scholar]
Cheson B D. Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol. 2010;28:3525-30.
[Google Scholar]
Wierda W G, Kipps T J, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011;117:6450-8.
[Google Scholar]
Czuczman M S, Hess G, Gadeberg O V, Pedersen L M, Goldstein N, Gupta I. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157:438-45.
[Google Scholar]
Stein R, Qu Z, Chen S, Rosario A, Shi V, Hayes M. Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin Cancer Res. 2004;10:2868-78.
[Google Scholar]
Morschhauser F, Leonard J P, Fayad L, Coiffier B, Petillon M O, Coleman M. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: Phase I/II results. J Clin Oncol. 2009;27:3346-53.
[Google Scholar]
Morschhauser F, Marlton P, Vitolo U, Lindén O, Seymour J F, Crump M. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol. 2010;21:1870-6.
[Google Scholar]
Sehn L H, Goy A, Offner F C, Martinelli G, Caballero M D, Gadeberg O. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467-74.
[Google Scholar]
Forero-Torres A, de Vos S, Pohlman B L, Pashkevich M, Cronier D M, Dang N H. Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcγRIIIa-genotyped patients with previously treated follicular lymphoma. Clin Cancer Res. 2012;18:1395-403.
[Google Scholar]
Weng W K, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940-7.
[Google Scholar]
Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754-8.
[Google Scholar]
Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Léger-Falandry C, Cogliatti S. Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: A study of the Swiss Group for Clinical Cancer Research (SAKK) Ann Oncol. 2005;16:1675-82.
[Google Scholar]
Tobinai K, Ogura M, Kobayashi Y, Uchida T, Watanabe T, Oyama T. Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci. 2011;102:432-8.
[Google Scholar]
Casulo C, Vose J M, Ho W Y, Kahl B, Brunvand M, Goy A. A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+indolent NHL: Correlation between clinical responses and AUC pharmacokinetics. Clin Immunol. 2014;154:37-46.
[Google Scholar]
Brown J R, Messmer B, Werner L, Davids M S, Mikler E, Supko J G. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Haematologica. 2013;98:964-70.
[Google Scholar]
Binder C, Ziepert M, Pfreundschuh M, Dührsen U, Eimermacher H, Aldaoud A. CHO (E) P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: Final analysis of a prospective phase II trial. Ann Hematol. 2013;92:1521-8.
[Google Scholar]
Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: Alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist. 2008;13:167-74.
[Google Scholar]
Hillmen P, Skotnicki A B, Robak T, Jaksic B, Dmoszynska A, Wu J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23.
[Google Scholar]
Kobayashi H, Matsunaga Y, Uchiyama Y, Nagura K, Komatsu Y. Novel humanized anti-CD20 antibody BM-ca binds to a unique epitope and exerts stronger cellular activity than others. Cancer Med. 2013;2:130-43.
[Google Scholar]
Vega M I, Martínez-Paniagua M, Huerta-Yepez S, González-Bonilla C, Uematsu N, Bonavida B. Dysregulation of the cell survival/anti-apoptotic NF-kappaB pathway by the novel humanized BM-ca anti-CD20 mAb: Implication in chemosensitization. Int J Oncol. 2009;35:1289-96.
[Google Scholar]
Nishida M, Uematsu N, Kobayashi H, Matsunaga Y, Ishida S, Takata M. BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties. Int J Oncol. 2011;38:335-44.
[Google Scholar]
Bowles J A, Wang S Y, Link B K, Allan B, Beuerlein G, Campbell M A. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood. 2006;108:2648-54. et al.
[Google Scholar]

Introduction

First-generation CD20 Monoclonal Antibody

Rituximab

Second-generation CD20 Monoclonal Antibody

Third-generation Monoclonal Antibody

Others

Fulltext Views
732

PDF downloads
436

View/Download PDF
Download Citations

BibTeX
RIS

Show Sections

[1] Illidge T, Cheadle E J, Donaghy C, Honeychurch J. Update on obinutuzumab in the treatment of B-cell malignancies. Expert Opin Biol Ther. 2014;14:1507-17.
[Google Scholar]

[2] Tedder T F, Engel P. CD20: A regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15:450-4.
[Google Scholar]

[3] Goldenberg D M, Morschhauser F, Wegener W A. Veltuzumab (humanized anti-CD20 monoclonal antibody): Characterization, current clinical results, and future prospects. Leuk Lymphoma. 2010;51:747-55.
[Google Scholar]

[4] Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi J F. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: Results of the GELA-GOELAMS FL2000 study. Blood. 2008;112:4824-31.
[Google Scholar]

[5] van Oers M H, Van Glabbeke M, Giurgea L, Klasa R, Marcus R E, Wolf M. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28:2853-8.
[Google Scholar]

[6] Marcus R, Imrie K, Solal-Celigny P, Catalano J V, Dmoszynska A, Raposo J C. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579-86.
[Google Scholar]

[7] Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-32.
[Google Scholar]

[8] Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-42.
[Google Scholar]

[9] Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12:1013-22.
[Google Scholar]

[10] Robak T, Robak E. New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies. BioDrugs. 2011;25:13-25.
[Google Scholar]

[11] Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004;104:3064-71.
[Google Scholar]

[12] Schulz H, Bohlius J F, Trelle S, Skoetz N, Reiser M, Kober T. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst. 2007;99:706-14.
[Google Scholar]

[13] Hainsworth J D, Litchy S, Barton J H, Houston G A, Hermann R C, Bradof J E. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-51.
[Google Scholar]

[14] Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012;5:64.
[Google Scholar]

[15] Alduaij W, Illidge T M. The future of anti-CD20 monoclonal antibodies: Are we making progress? Blood. 2011;117:2993-3001.
[Google Scholar]

[16] Czuczman M S, Gregory S A. The future of CD20 monoclonal antibody therapy in B-cell malignancies. Leuk Lymphoma. 2010;51:983-94.
[Google Scholar]

[17] Cheson B D. Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol. 2010;28:3525-30.
[Google Scholar]

[18] Wierda W G, Kipps T J, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011;117:6450-8.
[Google Scholar]

[19] Czuczman M S, Hess G, Gadeberg O V, Pedersen L M, Goldstein N, Gupta I. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157:438-45.
[Google Scholar]

[20] Stein R, Qu Z, Chen S, Rosario A, Shi V, Hayes M. Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin Cancer Res. 2004;10:2868-78.
[Google Scholar]

[21] Morschhauser F, Leonard J P, Fayad L, Coiffier B, Petillon M O, Coleman M. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: Phase I/II results. J Clin Oncol. 2009;27:3346-53.
[Google Scholar]

[22] Morschhauser F, Marlton P, Vitolo U, Lindén O, Seymour J F, Crump M. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol. 2010;21:1870-6.
[Google Scholar]

[23] Sehn L H, Goy A, Offner F C, Martinelli G, Caballero M D, Gadeberg O. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467-74.
[Google Scholar]

[24] Forero-Torres A, de Vos S, Pohlman B L, Pashkevich M, Cronier D M, Dang N H. Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcγRIIIa-genotyped patients with previously treated follicular lymphoma. Clin Cancer Res. 2012;18:1395-403.
[Google Scholar]

[25] Weng W K, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940-7.
[Google Scholar]

[26] Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754-8.
[Google Scholar]

[27] Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Léger-Falandry C, Cogliatti S. Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: A study of the Swiss Group for Clinical Cancer Research (SAKK) Ann Oncol. 2005;16:1675-82.
[Google Scholar]

[28] Tobinai K, Ogura M, Kobayashi Y, Uchida T, Watanabe T, Oyama T. Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci. 2011;102:432-8.
[Google Scholar]

[29] Casulo C, Vose J M, Ho W Y, Kahl B, Brunvand M, Goy A. A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+indolent NHL: Correlation between clinical responses and AUC pharmacokinetics. Clin Immunol. 2014;154:37-46.
[Google Scholar]

[30] Brown J R, Messmer B, Werner L, Davids M S, Mikler E, Supko J G. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Haematologica. 2013;98:964-70.
[Google Scholar]

[31] Binder C, Ziepert M, Pfreundschuh M, Dührsen U, Eimermacher H, Aldaoud A. CHO (E) P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: Final analysis of a prospective phase II trial. Ann Hematol. 2013;92:1521-8.
[Google Scholar]

[32] Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: Alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist. 2008;13:167-74.
[Google Scholar]

[33] Hillmen P, Skotnicki A B, Robak T, Jaksic B, Dmoszynska A, Wu J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23.
[Google Scholar]

[34] Kobayashi H, Matsunaga Y, Uchiyama Y, Nagura K, Komatsu Y. Novel humanized anti-CD20 antibody BM-ca binds to a unique epitope and exerts stronger cellular activity than others. Cancer Med. 2013;2:130-43.
[Google Scholar]

[35] Vega M I, Martínez-Paniagua M, Huerta-Yepez S, González-Bonilla C, Uematsu N, Bonavida B. Dysregulation of the cell survival/anti-apoptotic NF-kappaB pathway by the novel humanized BM-ca anti-CD20 mAb: Implication in chemosensitization. Int J Oncol. 2009;35:1289-96.
[Google Scholar]

[36] Nishida M, Uematsu N, Kobayashi H, Matsunaga Y, Ishida S, Takata M. BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties. Int J Oncol. 2011;38:335-44.
[Google Scholar]

[37] Bowles J A, Wang S Y, Link B K, Allan B, Beuerlein G, Campbell M A. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood. 2006;108:2648-54. et al.
[Google Scholar]

An update on newer monoclonal antibodies in lymphoma therapy

Abstract

Keywords

CD20 monoclonal antibody

lymphoma therapy

recent advances

Introduction

First-generation CD20 Monoclonal Antibody

Rituximab

Second-generation CD20 Monoclonal Antibody

Ofatumumab (HuMax-CD20; Arzerra)

Veltuzumab (IMMU-106, hA20)

Ocrelizumab (PRO70769)

Third-generation Monoclonal Antibody

Obinutuzumab (GA101)

Ocaratuzumab

PRO131921

Others

Alemtuzumab

BM-ca

Financial support and sponsorship

Conflicts of interest

References

Suggested read for related articles: