Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

Leonard, John P.; Goldenberg, David M.

doi:10.1038/sj.onc.1210370

Cited by 89 publications

(65 citation statements)

References 93 publications

(92 reference statements)

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“…Limited dosing might reduce the possible immune response to murine protein sequences in humanized antibodies, thus reducing adverse effects. 6 In other types of blood cell cancers such as chronic lymphocytic leukemia (CLL), which is characterized by low surface expression of CD22, the results with anti-CD22 antibodies are not as promising as in HCL, which is characterized by high CD22 surface level. 19 Therefore, more frequent infusions of optimal dosages might be necessary for treatment of CLL.…”

Section: Discussionmentioning

confidence: 99%

“…6 It induces rapid CD22 internalization. 20 Both inotuzumab ozogamicin and HA22-based immunotoxins rely on rapid internalization to deliver the cytotoxic payload to the cytoplasma of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of CD22 is seen in non-Hodgkin and other lymphomas. 5 Three therapeutic antibody candidates targeting CD22, epratuzumab, 6 inotuzumab ozogamicin, 7 and the fully recombinant immunotoxin BL22, 8 displayed efficacies in patients with B-cell malignacies. The unconjugated epratuzumab studied in clinical trials has the original murine CDRs grafted to a human antibody frame work.…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of fully human anti-CD22 monoclonal antibodies

Ho¹,

Zhu²,

Pastan³

et al. 2009

mAbs

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CD22 is a member of the B cell receptor family and is implicated in B cell function and development. It is expressed on multiple forms of B cell lymphoma and is an attractive cancer therapeutic target. We report here the identification of two fully human anti-CD22 antibodies using phage display methodology. Both antibodies exhibit specific binding to cell surface-associated CD22 in multiple B cell lines. Through ELISA using mammalian cell-expressed sub-domains of CD22 as binding antigen, we mapped the binding epitopes of the newly identified CD22 antibodies to be within the Ig-like domains 5 to 7 of CD22. Their epitopes do not overlap with those of several therapeutic antibodies currently in preclinical or clinical development. These antibodies have potential as cancer therapeutic candidates and research reagents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of fully human anti-CD22 monoclonal antibodies

Ho¹,

Zhu²,

Pastan³

et al. 2009

mAbs

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“…Antibodies and ADCs targeted to CD22 are being tested in clinical trials for efficacy in NHL. An unconjugated humanized anti-CD22 antibody, epratuzumab, is currently in clinical trials for the treatment of B-cell malignancies (10) and lupus (11). The ADC inotuzumab ozogamicin (IO, CMC-544) a human IgG4 monoclonal antibody to CD22 conjugated via an acid-labile hydrazone linker to a cytotoxic DNA-damaging agent calicheamicin (12,13) is being tested in clinical trials for treatment of NHL.…”

Section: Introductionmentioning

confidence: 99%

DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody–Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma

Poon

et al. 2013

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL.

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“…As a toxin component, these antibodies are linked to bacterial or plant toxins [8], RNases [9], ribosome inactivating proteins [10] or deflycosylating ricin A chains [11]. There is also a humanized monoclonal anti-CD22 antibody, Epratuzumab (LymphoCide R ), which was successfully tested in phase II clinical trials for non-Hodgkin lymphoma patients [12].…”

Section: Introductionmentioning

confidence: 99%

Human CD22 cannot fully substitute murine CD22 functions in vivo, as shown in a new knockin mouse model

2012

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CD22, an inhibitory co-receptor of the B-cell receptor, shows a B-cell-specific expression pattern and is expressed on most B-cell lymphomas. The anti-CD22 antibody Epratuzumab is in clinical trials for B-cell non-Hodgkin lymphoma and systemic lupus erythematosus, but shows a mostly unknown mode of action. We generated a new mouse model that expresses human CD22 instead of murine CD22 (Huki CD22 mice), in which human CD22 can be targeted. Expression of human CD22 on the B cells of Huki CD22 mice does not generally interfere with B-cell development. However, Huki CD22 mice show a reduction of the population of mature recirculating B cells in the bone marrow and reduced transitional and marginal zone B cells in the spleen, phenotypes resembling that of CD22-deficient mice. Similarly, enhanced BCR-induced Ca 2+ signalling is observed in Huki CD22 mice, which also mount normal immune responses toward different classes of antigens. Huki CD22 B cells show a normal anti-hCD22 antibody-mediated endocytosis. In conclusion, human CD22 cannot fully substitute for murine CD22 functions, possibly due to the changed intracellular tail of the protein or due to lower expression levels. Huki CD22 mice are a valuable new model for both antibody-and immunotoxin-mediated targeting of human CD22.Keywords: B-cell lymphoma r B-cell signalling r Siglecs r SLE Supporting Information available online IntroductionCo-stimulating proteins or co-receptors can modulate the B-cell receptor (BCR) signal. One of them is CD22, a member of the Siglec family (sialic acid binding immunoglobulin-like lectins). Siglecs bind to sialic acids, which are usually expressed on cell surfaces and in the extracellular milieu [1,2]. All Siglecs recognise sialic acids, but they vary in their affinity for different glycosidelinkages. CD22 prefers sialic acids in α2,6-linkage [3][4][5]. It is an Correspondence: Prof. Lars Nitschke e-mail: nitschke@biologie.uni-erlangen.de inhibitory co-receptor for BCR-induced calcium (Ca 2+ ) signalling. CD22 carries inhibitory ITIM-signalling motifs, which recruit the tyrosine phosphatase SHP-1 that is responsible for the inhibitory function of CD22. CD22 can bind to α 2,6-linked sialic acidcontaining ligands in cis and in trans. This ligand binding can modulate the signalling function of CD22 [3][4][5].The murine CD22 and the human CD22 protein share about 60% sequence homology. The human CD22 gene is located on chromosome 19 in the human genome, the mouse gene is located on chromosome 7. The human and the murine CD22 are expressed from the pre-B-cell stage to the mature B-cell stage. CD22 is downregulated on plasma cells [5]. It is also expressed on a majority of all B-cell lymphomas [6], for example, CD22 is expressed on 65% of the B-cell acute lymphoblastic leukaemia [7]. Differentwww.eji-journal.eu 3010 Miriam Wöhner et al. Eur. J. Immunol. 2012. 42: 3009-3018 immunotoxins use anti-CD22-antibodies to target these lymphoma and leukaemia cells. As a toxin component, these antibodies are linked to bacterial or plant toxin...

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Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

Cited by 89 publications

References 93 publications

Identification and characterization of fully human anti-CD22 monoclonal antibodies

Identification and characterization of fully human anti-CD22 monoclonal antibodies

DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody–Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma

Human CD22 cannot fully substitute murine CD22 functions in vivo, as shown in a new knockin mouse model

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