Tumour cell surface antigen targeted therapies in B-cell lymphomas: Beyond rituximab

Ku, Matthew; Chong, Geoff; Hawkes, Eliza A

doi:10.1016/j.blre.2016.08.001

Cited by 13 publications

(21 citation statements)

References 139 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Anest imated 20,000 patients died from non-Hodgkin lymphoma (NHL) in 2017 in the United States (1). B-cell NHLs constitute 85% of these cases, and 90% of B-cell lymphomas are B-lymphocyte antigen 20 (CD20)-positive (2,3). Although immunotherapies using anti-CD20 monoclonal antibodies (mAbs), including rituximab (Rituxan; Roche), have drastically improved patient outcomes, clinical resistance against unlabeled mAbs such as rituximab necessitates continued research, including different approaches to immunotherapy.…”

mentioning

confidence: 99%

“…Although tositumomab and rituximab are both the foundation of anti-CD20s radioimmunotherapies (although purely murine ibritumomab is the labeled component of the Zevalin therapy), they represent 2 different categories of anti-CD20 mAbs. Rituximab, a type I anti-CD20 mAb, promotes the formation of membrane lipid rafts, strongly activates complement-dependent cytotoxicity, and binds in a 2:1, mAb-to-antigen, stoichiometry (2,11). Tositumomab, a type II anti-CD20 mAb, does not aggregate lipid rafts, strongly activates homotypic adhesion, induces apoptosis instead of complement-dependent cytotoxicity, and binds antigen in a 1:1 stoichiometry (2,11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts

et al. 2018

View full text Add to dashboard Cite

Radioimmunotherapies with monoclonal antibodies to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but U.S. Food and Drug Administration-approved radioimmunotherapies exclusively use radiolabeled murine antibodies, potentially limiting redosing. The Food and Drug Administration recently approved 2 unlabeled anti-CD20 monoclonal antibodies, obinutuzumab and ofatumumab, termed next generation as they are humanized (obinutuzumab) or fully human (ofatumumab), thus potentially allowing a greater potential for redosing than with previous-generation anti-CD20 antibodies, including rituximab (chimeric) and tositumomab (murine), which contain more murine peptide sequences. We prepared Zr-ofatumumab andZr-obinituzumab and assessed their tumor targeting by PET/CT imaging and their biodistribution in a preclinical mouse model with CD20 xenografts to determine whether these antibodies have potential as theranostics or for radioimmunotherapy. Obinutuzumab, ofatumumab, rituximab, tositumomab, and human IgG (as control) were radiolabeled withZr. Raji Burkitt lymphoma xenografts were established in severe combined immunodeficient mice. Mice with palpable tumors ( = 4-9) were injected with Zr-obinutuzumab,Zr-ofatumumab, Zr-rituximab,Zr-tositumomab, or Zr-IgG, with small-animal PET/CT images acquired at 1, 3, and 7 d after injection, and then sacrificed for biodistribution analyses. At 1, 3, and 7 d after injection, all anti-CD20 antibodies showed clear tumor uptake on PET/CT, with minimal tumor uptake of IgG. Biodistribution data showed significantly ( < 0.005) higher tumor uptake for obinutuzumab (41.4 ± 7.6 percentage injected dose [%ID]/g), ofatumumab (32.6 ± 17.5 %ID/g), rituximab (28.6 ± 7.6 %ID/g), and tositumomab (28.0 ± 6.5 %ID/g) than IgG (7.2 ± 1.2 %ID/g). Tositumomab had much higher splenic uptake (186.4 ± 49.7 %ID/g, < 0.001) than the other antibodies. Zr-labeled obinutuzumab and ofatumumab localized to tumor as well as or better than labeled rituximab and tositumomab, 2 monoclonal antibodies that have been used previously in B-cell lymphoma radioimmunotherapy, and both obinutuzumab and ofatumumab have the potential for repeated dosing.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Immunotherapeutic targeting strategies, designed to exploit defined antigens expressed on the surface of leukemic cells, represent another avenue that has been extensively investigated in the pursuit of novel treatments for AML patients (7). Such antibody-based approaches have been transformative for the management of other hematologic malignancies, most notably B-cell lymphomas (8); however, their full clinical potential is yet to be realized within the context of AML.…”

Section: Introductionmentioning

confidence: 99%

IMGN779, a Novel CD33-Targeting Antibody–Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML

Kovtun

Noordhuis

Whiteman

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels., IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML. .

show abstract

“…2 Although therapies that include CD20 mAbs (usually in combination with chemotherapy) have proven to be effective, in almost all cases they are not curative. 3 In fact, often patients' tumors become refractory to additional CD20 therapy, and in several instances, this has been attributed to loss of CD20 from targeted B cells. 4 Therefore, there is a real need to enhance the potency of CD20 mAbs based on clearly delineating their mechanisms of action and the reasons for decreases in their efficacy.…”

mentioning

confidence: 99%

“…It was the first immunotherapy approved for specific use in cancer, and it quickly demonstrated a dramatic improvement in outcomes in patients with DLBCL when combined with chemotherapeutic agents. 2,3 Rituximab has since been approved for use in chronic lymphocytic leukemia, follicular lymphoma, and rheumatoid arthritis. It specifically targets CD20, which is expressed on normal B lymphocytes and on several types of malignant B cells.…”

mentioning

confidence: 99%

Rituximab immunotherapy: it’s getting personal

Phelps

2017

Blood

View full text Add to dashboard Cite

show abstract

Tumour cell surface antigen targeted therapies in B-cell lymphomas: Beyond rituximab

Cited by 13 publications

References 139 publications

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts

IMGN779, a Novel CD33-Targeting Antibody–Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML

Rituximab immunotherapy: it’s getting personal

Contact Info

Product

Resources

About

Tumour cell surface antigen targeted therapies in B-cell lymphomas: Beyond rituximab

Cited by 13 publications

References 139 publications

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with89Zr in Human Lymphoma Xenografts

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with89Zr in Human Lymphoma Xenografts

IMGN779, a Novel CD33-Targeting Antibody–Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML

Rituximab immunotherapy: it’s getting personal

Contact Info

Product

Resources

About

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with⁸⁹Zr in Human Lymphoma Xenografts