Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma

Rue, Sarah; Eckelman, Brendan P.; Efe, Jem; Bloink, Kristin; Deveraux, Quinn L.; Lowery, David E.; Nasoff, Marc

doi:10.1016/j.vetimm.2015.02.004

Cited by 50 publications

(48 citation statements)

References 29 publications

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“…A homolog of canine CD20 has been identified, and a speciated antibody to canine CD20 has been developed (7-9). Therefore, we began our investigation by examining the canine CD47-SIRPα interaction.…”

Section: Resultsmentioning

confidence: 99%

“…CV1-hIgG4 (11) and Hu5F9-G4 (30) were produced as previously described by expression in FreeStyle 293-F cells (Invitrogen) or CHO-K1 cells (Lonza). The native mouse antibody to dog CD20, 1E4, and chimeric mouse antibodies to CD20 on the canine IgGB background (IgG1 equivalent) Rtx-cIgGB and 1E4-cIgGB, were produced as described (9) and provided by Elanco Animal Health. For 1E4-cIgGB and Rtx-cIgGB ELISAs, binding to immobilized cCD20(ECD2)-hFc fusion protein was detected using a rabbit anti-canine IgG-HRP (US Biologicals #I1904-25Z) and Sure Blue TMB substrate (KPL) with absorbance measured at 650 nm in a Spectra Max (Molecular Devices).…”

Section: Methodsmentioning

confidence: 99%

“…Expression of CD20 in dogs on normal and malignant B cells is conserved, supporting the promise of CD20 as a therapeutic target in canine lymphoma (7, 8). Recently, a canine-specific CD20 mAb was developed with canine Fc regions (1E4-cIgGB) that effectively depletes normal B cells in healthy dogs and is undergoing investigation for canine B-cell lymphoma (9). …”

Section: Introductionmentioning

confidence: 99%

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Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Weiskopf

Anderson

Ito

et al. 2016

Cancer Immunology Research

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Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro. When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. Since robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47-blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Weiskopf

Anderson

Ito

et al. 2016

Cancer Immunology Research

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“…The tumor in this case was found to be B cell in origin, although immunocytochemistry was not performed so the value of specific anti-CD20 monoclonal antibodies cannot be determined. The use of these therapies is just beginning to be investigated in dogs, 32,33 and, at the time of writing, has not been investigated in cats but may offer improved survival in these species as well given the apparent similarities to the form of the disease seen in humans.…”

Section: Discussionmentioning

confidence: 99%

Primary adrenal lymphoma causing hypoaldosteronism in a cat

Romine¹,

Kozicki²,

Elie³

2016

Journal of Feline Medicine and Surgery Open Reports

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Case summaryA 10-year-old, 5.1 kg (11.2 lb), male castrated cat was presented with signs of lethargy and decreased appetite at home after being previously healthy. Serum biochemical analysis identified normokalemia (5.1 mmol/l; reference interval [RI] 3.4–5.6 mmol/l) and severe hyponatremia (123 mmol/l; RI 145–158 mmol/l), with an Na/K ratio of 24 (RI 32–41). Baseline serum cortisol was low to normal, but serum aldosterone was markedly decreased with a pre-adrenocorticotropic hormone stimulation concentration of 13 pmol/l (RI 194–388 pmol/l) and post-adrenocorticotropic hormone stimulation concentration of 21 pmol/l (RI 277–721 pmol/l). Hematologic and biochemical analyses were otherwise unremarkable. Abdominal ultrasound revealed bilaterally enlarged adrenal glands with no other abnormalities noted; thoracic radiographs also did not identify any signs of metastasis. Fine-needle aspiration was strongly suggestive of lymphoma of the adrenal glands, and PCR for antigen receptor rearrangement was positive for B-cell clonal expansion; based on these findings, a diagnosis of primary adrenal B-cell lymphoma was made. Stable disease was achieved for a short period of time following vincristine, cyclophosphamide, prednisolone and fludrocortisone therapy, followed by progressive adrenal enlargement and electrolyte derangements that responded to neither doxorubicin nor adjustments in fludrocortisone dosage. Ultrasonographic metastasis was not identified at any time, and other organ derangements were not noted on hematologic or biochemical analyses. The cat was euthanized 55 days after initial presentation.Relevance and novel informationThis is the first report of primary adrenal lymphoma in a cat, with presenting signs compatible with hypoaldosteronism. Lymphoma should be a differential for cats presenting with adrenal enlargement or clinical signs and biochemical changes consistent with hypoaldosteronism or hypoadrenocorticism.

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“…While this body of work, and studies that followed, demonstrated that canine IgGs consist of four subclasses, the diverse functions and interactions of canine immunoglobulins with other immune effector cells have remained less characterized [81]. Nevertheless, there has been a longstanding interest in canine specific mAbs, including canine-CD20 targeted antibodies, for therapeutic and diagnostic use [66, 68, 69]. Important for cross-species translational studies, Bergeron et al demonstrated that canine Fc gamma receptors bind to dog, human, and mouse IgGs, suggesting that a human therapeutic antibody could be effective at stimulating ADCC in a canine therapeutic model, although species differences may result in significant differences in activity as well as eventual neutralization by the host [81].…”

Section: Introductionmentioning

confidence: 99%

Canine cancer immunotherapy studies: linking mouse and human

Park¹,

Withers²,

Modiano³

et al. 2016

j. immunotherapy cancer

100

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Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.

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Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma

Cited by 50 publications

References 29 publications

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20

Primary adrenal lymphoma causing hypoaldosteronism in a cat

Canine cancer immunotherapy studies: linking mouse and human

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