Monoclonal Antibodies

Two humanized monoclonal antibodies to lymphoid differentiation antigens—CD52 and CD20—were tested in CLL patients. Clinical trials recently began for another humanized monoclonal antibody, Hu1D10. A fourth humanized monoclonal antibody reactive with CD47 is under development. The anti-CD20 and anti-CD52 antibodies showed significant antileukemic activity (Table 2).

The humanized antibody to CD52—Campath 1H, or alemtuzumab—showed a response rate of approximately 80% in untreated patients or 40% in patients who had previously received cytotoxic chemotherapy (45-49). Most of these responses were partial remissions lasting less than 1 yr. Furthermore, clearing of disease was seen in the blood and bone marrow but not lymph node sites. The limited activity in CLL may be owing to low antigen density (50). Side effects included a high rate of infection and a cytokine release syndrome. These complications may be

Table 1

Cell Surface Molecules Found on CLL Cells

Table 1

Cell Surface Molecules Found on CLL Cells

Antigen

Properties

Function

Distribution

Ref.

IL-4 receptor

p140a; p64g

B-cell activation

Heme + cross-reaction IL-13R on

14

multiple tissues

1D10

Variant HLA-DRb

Apoptosis regulation

B-cells

15

CD5

p67

ITIM co-receptor

Lymphoid (T + B)

16

CD18

p100

P2-integrin

Heme

17

CD19

p95

ITAM co-receptor

B-cells

18

CD20

p35

B-cell differentiation/proliferation regulation

B-cells

19

CD21

p145

C3d/EBV receptor

B-cells

20

CD22

p150

ITIM co-receptor

B-cells

21

CD23

p45

FceRII/CD40 binding

Heme + epithelia

22

CD24

p40 2-chain GPI-linked

Adhesion (binds CD62P)

Heme +neurons + muscle + skin +

23

mucin glycoprotein

carcinomas

CD25

p55

IL-2Ra

Heme

24

CD27

p110 disulfide-linked

Costimulatory with CD70

Lymphoid (T + B)

25

dimer; member TNFR

CD29

p130

Pl-integrin

Most animal and plant cells but not red

26

blood cells

CD38

p45

NAD glycohydrolase; adhesion; signaling

Heme + epithelia

27

CD43

p145 sialoglycoprotein

Antiadhesive/adhesive

Heme

28

CD44

p85 glycoprotein with

Receptor hyaluronic acid; adhesion

Heme + epithelia + endothelia

29

multiple splice variants

CD45

p180-220

Receptor tyrosine phosphatase

Heme

30

CD47

p50 N-linked glycan

Thrombospondin receptor; integrin regulator

Heme + epithelia + endothelia + fibroblasts

31, 32

CD49d

p140

a4-integrin

Heme

(continued)

Table 1 (continued)

Antigen

Properties

Function

Distribution

Ref.

CD50

p110

ICAM-3; binds LFA-1; costimulatory

Heme + endothelium

34

CD52

p20 GPI-linked

Unknown

Lymphoid (T + B) + sperm

35, 36

glycoprotein

CD54

p100

ICAM-1; binds LFA-1

Heme + endothelium

37

CD55

p70 GPI-linked

DAF; interferes with complement

Heme + endothelium

38

glycoprotein

CD59

p19 GPI-linked

MACIF; membrane attack complex inhibition

Heme + endothelium

39

glycoprotein

CD62L

p80

LECAM-1; leukocyte-endothelium adhesion

Lymphoid (T + B)

40

CD70

p50/70/90/100/160

Costimulatory with CD27

Lymphoid (T + B)

41

CD72

p43

A CD5 receptor; ITIM co-receptor

B-cells

42

CD79b-truncated

p50

Immunoglobulin antigen receptor-defective

B-cells

13, 43

CD102

p200

ICAM-2; binds LFA-1

Heme + endothelium

44

CLL, chronic lymphocytic leukemia; DAF, decay-accelerating factor; EBV, Epstein-Barr virus; GPI, glycosylphosphatidylinositol; ICAM, intercellular adhesion molecule; IL-2Ra, interleukin-2 receptor a; ITAM, immunoreceptor tyrosine activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; LECAM, leukocyte endothelium cell adhesion molecule; LFA, leukocyte factor-association antigen; MACIF, membrane attach complex inhibitory factor; NAD, nicotinamide adenine dinucleotide; TNFR, tumor necrosis factor receptor.

CLL, chronic lymphocytic leukemia; DAF, decay-accelerating factor; EBV, Epstein-Barr virus; GPI, glycosylphosphatidylinositol; ICAM, intercellular adhesion molecule; IL-2Ra, interleukin-2 receptor a; ITAM, immunoreceptor tyrosine activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; LECAM, leukocyte endothelium cell adhesion molecule; LFA, leukocyte factor-association antigen; MACIF, membrane attach complex inhibitory factor; NAD, nicotinamide adenine dinucleotide; TNFR, tumor necrosis factor receptor.

Monoclonal Antibodies, Radioimmunoconjugates, and Drug Conjugates for Treatment of CLL

Agent

Disease status

Response (%)

Comments

Ref.

Alemtuzumab

Untreated

89

100% response in blood and 32% in nodes; response durations 8+ - 24+ mo; treatment 30 mg ti wk x 18

45

Relapsed/refractory

42

97% response blood, 36% response of splenomegaly, 7% response in nodes; mean response duration 12 mo

46

Refractory

33

82% response without adenopathy and 25% with adenopathy; infections in 56% of patients

47

Refractory

59

10% showed negative minimal residual disease by flow/PCR and remain in remission >2-3 yr

48

Refractory

20

3% complete remission; 18% fever, chills, hypotension, dyspnea; 24% infections; 12% rash

49

Rituximab

Relapsed/refractory

7

1/15 patients with a partial response to 375 mg/m2/wk a 4

55

Relapsed/refractory

39

500 mg/m2-2000 mg/m2; dose-dependent response; effect on blood, nodes, and organs but less effect on marrow

56

Relapsed/refractory

46

250-375 mg/m2 ti wk a 12 doses; 3/27 thrombopenia; poor marrow response;

57

response correlated with CD20 level

2 2 2 Flud. 25 mg/m /cytoxan 250 mg/m d 2-4 + rituximab 375 mg/m d 1 course 1

and 500 mg/m d 1 courses 2-6 qmo

Untreated

94

58

Relapsed/refractory

70

Same combination schedule as above; 17% serious infections or fever; CR 14%

59

90Y-T101

131t t

I-Lym-1

vs 57% in above trial

Advanced/refractory

100

1/1 partial response lasting 6 mo; significant bone marrow suppression

66

Advanced

80

4/5 partial remissions and 1/5 complete remission; thrombopenia

67

B43-genistein

Relapsed

0

0/1 response

72

CLL, chronic lymphocytic leukemia; CR, complete response; Flud., fludarabine; PCR, polymerase chain reaction.

CLL, chronic lymphocytic leukemia; CR, complete response; Flud., fludarabine; PCR, polymerase chain reaction.

caused by the expression of CD52 on all hematopoietic cells including granulocytes and monocytes. CD16-positive natural killer cells bind antibody and release tumor necrosis factor-a (TNF-a) and IL-6 (51-53). Based on the promising response rate and evidence of a unique mechanism of programmed cell death in vitro (54), combination protocols with myeloid growth factors or cytotoxic chemotherapy are being started.

The humanized anti-CD20 monoclonal antibody rituximab has been used for treatment of CLL patients (55-59). The response rate was only 12% in relapsed/refractory CLL patients, which may be attributable partly to low CD20 antigen density and low circulating rituximab levels in treated patients (60,61). Further, few responses were seen in the marrow, possibly partly because of anti-apoptotic signals from bone marrow stroma to the CLL stem cells (62). Increasing the dose intensity, by raising the dose or shortening the interval between doses, led to an improvement in response rate to 40%. Combining rituximab with chemotherapy produced a dramatic increase in response rate and in the number of complete remissions; rituximab + chemotherapy may produce a supra-additive cytotoxicity to CLL cells (63).

Hu1D10 is a humanized antibody to the 1D10 antigen. This antigen is a variant HLA-DRb chain. In an on-going phase I study with relapsed non-Hodgkin's lymphoma patients, some partial responses have been seen (64). Extensive phase I/II studies in CLL patients are planned.

Antibody to CD47 induces CLL cell apoptosis (31). Efforts are under way to prepare a humanized version of this antibody for clinical testing. The anti-CD22 humanized monoclonal antibody epratuzumab has been tested in refractory large cell lymphoma (65). There are no reports of its use in CLL. The weak expression of CD22 on CLL cells may impact on its activity.

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