IJMCM Summer 2015, Vol 4, No 3

Review Article

Anti-CD19 Monoclonal Antibodies: a New Approach to Lymphoma Therapy Fatemeh Naddafi1, Fatemeh Davami2∗ 1. Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Submmited 7 March 2015; Accepted 25 May 2015; Published 21 July 2015

CD19 is expressed on B- lineage cells and follicular dendritic cells and plays a key role in B cell malignancies and autoimmune diseases. Thus, it has been considered as potential target for several monoclonal antibodies (mAbs). For decades, chemotherapy has been known as one of the major antitumor therapies eradicating high proliferative tumor cells. But, anti- CD19 mAbs developed for treating CD19- positive lymphomas and autoimmune diseases would rank among the most novel area of research and development in the pharmaceutical industry. Moreover, several anti- CD19 mAbs are currently being tested in various clinical trials and this review provides an overview of the research accomplished so far. Key words: Anti-CD19, monoclonal antibodies, B-cell lymphoma, anti-CD19 sFv, blinatumumab

A

cute leukemia is considered as the most

the immunoglobulin (Ig) superfamily and can act as

common form of childhood malignancies (1),

a central positive response regulator in B cells (6,

accounting for 20–30% of all pediatric malignan-

7). The CD19 has been expressed on the surface of

cies depending on age (2). In the United States,

leukemia cells in > 90% of cases with acute

about 2500 new patients are diagnosed annually;

lymphoblastic leukemia (ALL). Moreover, it can be

and 80% of these patients are B-lineage acute

expressed on tumor cells of cases with both B-cell

lymphoblastic leukemia (B-ALL) (1). In western

NHL and chronic lymphocytic leukemia (CLL).

countries, high incidence rates of non–Hodgkin's

Thus, CD19 antigen is an ideal target for

lymphoma (NHL) have been reported, and most of

immunotherapy of B-cell malignancies (8, 9).

NHL subtypes are more prevalent among men than

CD19 can act as a B cell co-receptor in conjunction

women (3). The fifth most common cancer in the

with both CD21 and CD81 (10). Genetic studies

United States is NHL and >66,000 patients have

show that CD19 has a role in keeping a balance

been diagnosed with NHL in 2008 (4). NHL is

between

accounting for about 4% of all cancer diagnoses in

Although both CD19 and CD22 have their own

incidence and deaths annually (5). CD19 is a 95-

regulatory network, they do not modulate B cell

kDa transmembrane glycoprotein which belongs to

receptor (BCR) signals independently. CD19

∗

immunity

and

autoimmunity

Corresponding author: Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. E-mail: [email protected]

(10).

Naddafi F and Davami F

modulates CD22 phoshoryla-tion by increasing Lyn

indicates encouraging activity in indolent and

kinase activity, while CD22 suppresses CD19

aggressive NHL with 33% error at the maximum-

phosphorylation

tyrosine

tolerated dose (MTD). Moreover, the lack of

phosphatase-1 (SHP-1). This ‘‘CD19/CD22 loop’’

remarkable myelosuppression makes it an attractive

could be directly related to an autoimmune

mAb to be combined with chemotherapy drugs.

phenotype in mice, so that it could be an attractive

Both pre and post treatment have revealed DM4

therapeutic target for regulating B cell signaling in

assembly in tumor and a decline in CD19 protein

autoimmune

various

expression level. These data demonstrate promising

antibody-based therapies targeting CD20 including

clinical activity of SAR3419 in NHL (16). Thus, it

rituxan® (rituximab) are on the market (11), anti

could be a promising drug in patients who were

CD19 monoclonal antibodies (mAbs) have lately

refractory to rituximab (17). Furthermore, in

been advanced into clinical trials. Many anti-CD19

preclinical studies, SAR3419 has been identified as

IgG1 antibodies with cytotoxicity-improved Fcγ

a novel and well-tolerated therapeutic agent in B-

part and three drug conjugated antibodies including

cell NHL (4). It has been reported that SAR3419

coltuximabravta-nsine (SAR3419), denintuzumab-

delays the progression of four CD19+ B-cell

mafodotin and taplitu-momabpaptox are now in

precursor-ALL and three of three mixed lineage

phase 1/2 trials (5, 12) and the most advanced is the

leukemia-ALL

anti-CD19/CD3 BiTE antibody blinatumumab,

responses in all but one xenograft. But it cannot be

which is in phase 1 trial in patients with NHL (13,

effective

14) and was approved for Precursor B-cell acute

SAR3419 can exert remarkable efficacy against

lymphoblastic leukemia (B-cell ALL) on December

chemoresistant B-cell precursor-ALL xenografts

3, 2014 (12). Antibody drug conjugates (ADCs)

over a high dose range (10-fold) and delayed

comprise an antibody which is joined to a cytotoxic

vincristine/dexamethasone/L-asparaginase (VXL)-

drug by a linker. ADCs could join the specificity of

induced leukemia progression in two chemore-

a monoclonal antibody (mAb) to the cytotoxicity of

sistant xenografts by up to eighty two days (18). In

a small molecule drug .Thus, they are promising

prolonged treatment which is following remission

new therapeutic anticancer drugs. Currently, there

induction with VXL, SAR3419 may inhibit disease

are over 30 ADCs that are being investigated in

recurrence into hematolymphoid without central

early or late stage of clinical trials (15) (Table 1)

nervous system involvement. These data confirm

(Fig. 1, 2).

that the involvement of SAR3419 into remission

Anti-CD19 monoclonal antibodies in clinical

induction protocols improve the outcome for both

development

pediatric and adult CD19+ ALL (18).

SAR3419

MOR-208

through

diseases

SH-protein

(7).

Although

xenografts,

against

T-lineage

causing ALL

objective xenografts.

SAR3419 (huB4-DM4), is a humanized IgG1

MOR-208 (XmAb5574) is in phase 2 and was

anti-CD19 antibody which is attached via a

developed by Xencor and MorphoSys AG as a

disulfide

linker

potent

cell-

killing

therapeutic drug for NHL and ALL (12). XmAb-

drug,

DM4,

which

5574 is a humanized mouse antibody with an

and

engineered Fc domain with two amino acid

microtubule assembly in the G2/M phase of the

substitutions S239D and I332E that increases its

mitotic cycle and as a consequence, can cause

cytotoxic potency by binding to Fcγ receptors IIIa

apoptotic cell death (5). SAR3419 is in phase 1 trial

on immune cells and reduces binding to FcγRIIb.

for CD19+ NHL histological subtypes and it

Both in vitro and in vivo studies have shown that

maytansinoid prevents

both

to

a

derivative tubulin

polymerization

Int J Mol Cell Med Summer 2015; Vol 4 No 3 144

Anti-CD19 and Lymphoma Therapy

XmAb5574 increases antibody dependent cell-

modulated by natural killer (NK) cells via a

mediated cytotoxicity (ADCC) 100-fold to 1,000-

granzyme

fold which confirms its anticancer effects against a

XmAb5574 can functionally activate both NK-cell

wide range of B-lymphoma (19). In another study,

lysosomal

the administration of XmAb5574 to cynomolgus

(CD107a) production and IFN-γ secretion. Erk1/2

monkeys demonstrated a decline of B cells in the

belongs to the mitogen-activated protein kinase

lymphoid tissues. Moreover, a decrease in peri-

family that is serine-threonine kinases and its

pheral NK-cell levels and loss of the maximal rate

phosphorylation is essential to FcγRIIIa-induced

of B-cell have been found. It has also been

granule exocytosis in NK cells. NK cells stimula-

munifested that XmAb5574 couples to monkey

tion in the presence of XmAb5574 leads to up-

CD19 and demonstrates increased binding to FcγRs

regulation of Erk1/2 phosphorylation (19).

B–dependent associated

mechanism membrane

(19).

protein-1

(20). The XmAb5574-dependent ADCC can be Table 1. A brief overview of anti – CD 19 mAbs. Antibody

Internal name AMG103

Antigen

Company

Phase

Condition

Antibody type

CD19,C D3

Amgen

Approved 1

ALL NHL

Coltuximabravt ansine

SAR341 9, huB4DM4

CD19

ImmunoGen Inc. Sanofiaventis

2 1

ALL, NHL

MOR208

XmAb 5574

CD19

2 1

ALL, NHL CLL

MEDI-551

MEDI551

CD19

Morphosys AG, Xencor Inc. Medimmune

Mouse/ bispecificsc FvCD19× CD3 (BiTE) Humanized mouse antibody drug conjugate/IgG1 Humanized mouse antibody

2

B-cell malignancies, CL L, Multiple Myeloma, Scleroderma

Humanized mouse antibody

Denintuzumab mafodotin

SGN19A, SGNCD19A, BU12 B4, DIB4 Taplitum omabpap tox XmAb 5871

CD19

Seattle Genetics

1

NHL

Humanized undefined source antibody drug conjugate/IgG1

CD19

Merck Serono National Cancer Institute Amgen, Xencor Inc.

1

B-cell malignancies B-cell malignancies

1

Autoimmune Diseases

Humanized mouse antibody Mouse antibody drug conjugate/IgG1 Humanized undefined source antibody Human-from transgenic mouse antibody Human bispecific antibody

Blinatumomab

Merck patent anti-CD19 Taplitumomabp aptox XmAb 5871

CD19

CD19

1

MDX-1342

MDX1342

CD19

Medarex

1

CLL,Rheumato id Arthritis

AFM11

AFM11

CD19, CD3

Affimed

1

NHL

CD: cluster of differentiation; ALL: acute lymphoblastic leukemia; BiTE: bispecifc T cell engager; CLL: chronic lymphocytic leukemia; NHL: non-Hodgkin lymphoma.

145 Int J Mol Cell Med Summer 2015; Vol 4 No 3

Naddafi F and Davami F

Fig. 1. Anti CD19 mAbs types.

Fig. 2. Anti CD19 mAbs in clinical trials.

MEDI-551

clear cell samples in an autologous ADCC assay

MEDI-551 can target CD19 on B cells and

(21). Both blood and tissue B cells in human

entered phase 2 trial in 2011. MEDI-551 was

CD19/CD20 double transgenic (Tg) mice have been

developed

novel

in lower concentrations than that of the positive

afucosylated anti-human (hu) CD19 mAb, MEDI-

control mAb rituximab. Furthermore, macro-phage-

551 has been produced with high affinity to human

mediated phagocytosis and complement-dependent

FcγRIIIA and mouse FcγRIV and increased ADCC.

cytotoxicity might have a role in depletion with

MEDI-551 was highlighted to be effective at much

rituximab in huCD19/CD20 Tg mice (21). B-cell-

lower mAb concentrations than the fucosylated

depleting activity of MEDI- 551 has been

parental mAb anti-CD19-2 in in vitro ADCC assays

demonstrated in both in vitro and in vivo studies

with B-cell lines. Moreover, it has been proven that

and could be a promising novel drug for the

the afucosylated CD19 mAb MEDI-551 reduced B

treatment of both B-cell malignancies and auto-

cells from normal donor peripheral blood mononu-

immune diseases (21). MEDI-551 is effective in

by

Medimmune

(12).

A

Int J Mol Cell Med Summer 2015; Vol 4 No 3 146

Anti-CD19 and Lymphoma Therapy

tumor growth inhibition in multiple preclinical

a target for the treatment of new autoimmune

mouse xenograft models and has profound activity

diseases. It has been shown that the coengagement

in combination with the CD20 mAb rituximab (22).

of BCR and FcγRIIb through the Fc-engineered

It has been found that MEDI -551 treatment of

anti-CD19 XmAb5871 inhibits humoral immune

severe combined immunodeficiency (SCID) mice

responses (26). XmAb5871 declines both ERK and

engrafted with human pre-B cells caused long term

AKT activation, cell proliferation, cytokine, and

animal survival and as a consequence decreased

IgG synthesis that are induced by both BCR and

disease burden in blood, liver and bone marrow.

TLR9 signals. Moreover, XmAb5871 suppresses

These studies indicate that anti-CD19 antibodies

differentiation

strongly recruit immune cells to precursor-B ALL

plasma cells from rheumatoid arthritis cases. Thus,

cells and can enter to early phase trials in pre-B

XmAb5871

acute lymphoblastic leukemia (23). Single-agent

suppression of pathogenic B cells in autoimmune

activity with a manageable toxicity profile has been

diseases

found in CLL cases treated in phase 1/2 trial

XmAb5871 causes phosphorylation of the ITIM of

of MEDI-551. A phase 2 study of MEDI-551

FcgRIIb

combined with bendamustine in relapsed CLL cases

mobilization,

(NCT01466153) is investigating clinical response

expression of human B cells from both healthy

to both MEDI-551 and chemotherapy (24).

donors and systemic lupus erythematosus (SLE)

SGN-CD19A

cases (29), and also B cell proliferation stimulated

Since CD19 has been expressed in most B-cell

of can

(26-28). and

citrullinated

peptide-specific

play potential It

inhibits

has

been

role

proven

BCR-induced

proliferation,

and

in

the that

calcium

costimulatory

by lipopolysaccharides (LPS), interleukin 4 (IL-4),

(SGN-

or B-cell activating factor (BAFF). Furthermore,

CD19A) can be a novel antibody-drug conjugate

XmAb5871 inhibits humoral immunity against

consisting of a humanized anti-CD19 mAb attached

tetanus toxoid and declines serum IgM, IgG, and

to the microtubule-disrupting agent monomethyla-

IgE levels in SCID mice which are engrafted with

uristatin F (MMAF) through a maleimidocaproyl

either SLE or healthy human peripheral blood

linker. SGN-CD19A has indicated signs of clinical

mononuclear cells (PBMCs) (29). Treatment with

activity with an objective response rate (ORR) of

XmAb5871 led to an increase in the survival of

40% (8 of 20 cases) and an observed complete

mice engrafted with PBMCs from a unique SLE

response rate of 30% (6 of 20 cases). No dose-

donor. It has been evidenced that coengagement of

limiting toxicity was found in tested doses and

both FcgRIIb and BCR complex could not increase

further studies are needed to determine the optimal

B cell depletion in human PBMCs cultures or in

dose of SGN-CD19A (25).

mice. Thus, stimulation of the FcgRIIb inhibitory

XmAb5871

pathway in activated B cells can be an attractive

NHL

patients,

denintuzumabmafodotin

XmAb5871 is a humanized Fc engineered

therapeutic approach for the treatment of systemic

antibody attached to FcgRIIb with approximately

lupus

erythematosus

400-fold higher affinity compared with its native

diseases (29).

IgG1 Fc (26). XmAb5871 which was generated by

MDX-1342

and

other

autoimmune

both Amgen and Xencor Inc, entered phase 1 trial

MDX-1342 is a human anti- CD19 antibody

for autoimmune diseases in 2011 (12). The Fc

which entered phase1 trial for chronic lymphocytic

receptor (FcγRIIb) could suppress B cell responses

leukemia in 2008 and was supported by Medarex

when coengaged with BCR. Thus, it is identified as

(Bristol-Myers Squibb). A phase 1 trial for rheuma-

147 Int J Mol Cell Med Summer 2015; Vol 4 No 3

Naddafi F and Davami F

toid arthritis was completed in June 2013 (12).

which is composed of two single chain antibodies

MDX-1342 is able to bind to human CD19-

(scFvs) to both CD19 and CD3 that are connected

expressing cells, which is similar to its fucosylated

via a flexible linker (32-34). Blinatumomab was

parental antibody. MDX-1342 has an increased

developed by Micromet and entered phase 1 for

affinity for both FcγRIIIa-Phe158 and FcγRIIIa-

NHL in 2004 (12). It was approved by FDA for

Val158 receptors. Moreover, an increased effector

precursor B-cell ALL therapy on December 3,

cell function has been indicated by enhanced

2014 This bispecific T-cell-engaging antibody, can

efficacy in ADCC assay. Furthermore, its low

couple polyclonal T cells to CD19-expressing B

nanomolar binding to cynomolgus monkey CD19

cells and bring both T cells and malignant B cells in

and enhanced affinity for cynomolgus monkey

close proximity. As a consequence, it induces

FcγRIIIa is found. In vivo studies have indicated

killing of malignant B cells (34). It has been found

that MDX-1342 in cynomolgus monkeys leads to

that

potent B-cell depletion. Thus, MDX-1342 can be

blinatumomab and rituximab leads to a potent

considered as a B-lymphocyte depletive therapy for

activation of pro-caspases 3 and 7 in target cells,

both malignancies and autoimmune diseases (30).

which could result in the induction of granzyme-

MDX-1342 has comparable effects with rituximab

mediated apoptotic cell death (35). Although the

for in vivo B-cell depletion. When these mAbs are

comparative studies proved that the cytotoxic

administered as a single dose, both extent and

activity caused by blinatumomab with T cells is

duration of blood B-cell depletion is comparable,

considerably more than ADCC by rituximab, the

but the onset of depletion with rituximab is more

combination of both rituximab and blinatumomab

rapid (21).

increases the activity of rituximab, particularly at

AFM11

low effector-to-target cell ratios and at low antibody

the

cytotoxicity

modulated

by

both

AFM11 is a human bispecific antibody which

concentration (35). In an in vitro study, blinatumo-

entered phase 1 trial in 2014 and was developed by

mab was cocultured with NALM-6, the CD19-

Affimed Therapeutics AG as a therapeutic drug for

expressing pre-B lymphoma cell line, and CD8-

NHL (12). AFM11 recruits T cells to kill CD19-

expressing T cells. Consequently, it increased cell

positive cells and in vitro studies indicate a much

contact with both T and NALM-6 cells and

higher potency and efficacy of tumor cell lysis by

enhanced apoptosis and lysis of NALM-6 cells (33,

AFM11 compared with a bispecific tandem scFv. In

34). Cell lysis was not found in CD19- negative

addition, in vivo analysis of AFM11 shows a dose-

malignancies particularly, an erythroleukemia cell

dependent growth inhibition of Raji tumor cells and

line 28 and a colon cancer cell line 29, indicating

a single dose of AFM11 shows similar efficacy as 5

that CD3 binding by blinatumomab alone is not

daily injections (31). It has been found that AFM11

sufficient to cause T- cell activation. In the absence

can activate T cells only in the presence of CD19-

of major histocompatibility complex class I

positive cells. In peripheral PBMCs cultures,

expression, T-cell-mediated cell lysis has been

AFM11 has been seen to induce both CD69 and

maintained (33, 34). Blinatumomab recruits all

CD25 expression, T cell proliferation, and secretion

cytotoxic T cells for lysis of cancer cells. In NHL

of IFN-γ, TNF-α, IL-2, IL-6, and IL-10. Thus,

cases who

received

doses as low as

0.005

2

AFM11 could be a promising drug for the treatment

mg/m /day, an elimination of target cells in blood

of CD19- positive tumors (31).

was reported. Both partial and complete tumor

Blinatumomab

regressions were first found at a dose level of 0.015

Blinatumomab is a 55 kDa fusion protein

mg and a tumor regression was seen in all seven

Int J Mol Cell Med Summer 2015; Vol 4 No 3 148

Anti-CD19 and Lymphoma Therapy

cases who received a dose level of 0.06 mg.

entire evaluable cohort of 20 cases was 61%. In

Furthermore, blinatumomab could cause tumor cell

addition, the hematologic relapse-free survival rate

clearance from bone marrow and liver (36).

of 9 cases that were given allogeneic hematopoietic

Blinatumomab-expanded T cells (BET) have been

stem cell

proven to have normal expression of the synapse

treatment was 65%. In conclusion, blinatumomab

inhibitors CD272 and CD279 in comparison with

could induce long-term complete remission in B-

starting T cells and could be cytotoxic against

lineage ALL cases with either persistent or

CD19+ targets in the presence of blinatumomab in

recurrent MRD. Furthermore, blinatumomab is

vitro. It has been found that a combination of BET

known as an efficacious and well-tolerated therapy

and blinatumomab have remarkable therapeutic

in MRD-positive B-lineage ALL cases after

effect in a systemic human diffuse large B

intensive chemotherapy. Coengagement of both T

lymphoma model in NOD-SCID mice. Thus, BET

cells

can be identified as a therapeutic tool for

chemotherapy-resistant tumor cells that drive

immunoreconstitution of heavily immunosuppres-

clinical relapse (40).

sed CLL cases and, in combination with blinatumo-

Conclusion

transplantation

and

after

blinatumomab

blinatumomab could

eradicate

mab, could be considered as anti-tumor immuno-

The CD19 antigen can be expressed on the

therapy (37). After the start of infusion in patients

surface of leukemia cells in patients with ALL and

treated with blinatumomab, a rapid drop in

NHL. Thus, it could be the main target for anti-

peripheral T cell counts has been reported and also

CD19 mAbs. Therapy with mAbs has been

an expansion above baseline counts was found

developed in the last decade, due to their

during the treatment. In addition, binding of

mechanisms of action and side-effects. Since

blinatumomab to both T and Raji lymphoma cells

bispecific

could lead to CD69 up-regulation on activated T

which brings a cytotoxic T cell and the cancer

cells surface (38). After a median of 398 days

target cell in close proximity and effectively

follow-up of posttransplant relapsed pediatric cases

eradicates tumor cells, has been investigated and

with

given

indicated high response rates in cases with both

blinatumomab as a four week continuous intra-

NHL and ALL, it is considered as promising B-

B-precursor

ALL,

who

were

2

antibodies

including

blinatumumab,

venous infusion at a dosage of 5 or 15 µg/m /day,

lineage anti-tumoral drug tested in various clinical

the probability of hematologic event-free survival

trials for NHL and ALL and is the first anti-CD19

has been reported to be 30%. Moreover, major

approved drug for precursor B-cell ALL in

toxicities were grade three seizures in one case and

December 2014. Anti-CD19 monoclonal antibodies

grade three cytokine release syndrome in two cases.

that are in phase 1/2 clinical trials are expected to

It has been found that blinatumomab can induce

be advanced into clinical development in the future.

molecular remission in pediatric cases with

Conflict of Interests

posttransplant relapsed B-precursor ALL (39). It

The authors declared no conflict of interests.

has been illustrated that blinatumomab can induce an 80% minimal residual disease (MRD) response

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