Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

Sherbenou, Daniel W.; Aftab, Blake T.; Su, Yang; Behrens, Christopher R.; Wiita, Arun P.; Logan, Aaron C.; Acosta‐Alvear, Diego; Hann, Byron; Walter, Peter; Shuman, Marc A.; Wu, Xiaobo; Atkinson, John P.; Wolf, Jeffrey L.; Martin, Thomas G.; Liu, Bin

doi:10.1172/jci85856

Cited by 84 publications

(97 citation statements)

References 60 publications

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“…Saporin is a very stable cytotoxic drug that functions by preventing protein synthesis in the cell. It has been used to induce apoptosis of tumour cells in cancer therapies . The potential off‐target effect of ADC treatment was a concern, as splenic CD11c + CD11b + cells expressed the second highest level of CX 3 CR1, but we found that the activated T cells in the spleen and the levels of circulating antibodies including anti‐dsDNA antibodies were not different between ADC‐ and PBS‐treated groups.…”

Section: Discussionmentioning

confidence: 60%

Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Liao

Ren

Reihl

et al. 2017

Clinical and Experimental Immunology

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Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40-60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus-prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus-prone mouse models, we showed the pathogenic role of a kidney-infiltrating CD11c myeloid cell population in LN. These CD11c cells accumulated in the kidneys of lupus-prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C) mature monocytes. The cytokine/chemokine profile of these renal-infiltrating CD11c cells suggests their roles in promoting LN, which was confirmed further in a loss-of-function in-vivo study by using an antibody-drug conjugate (ADC) strategy targeting CX CR1, a chemokine receptor expressed highly on these CD11c cells. However, CX CR1 was dispensable for the homing of CD11c cells into lupus nephritic kidneys. Finally, we found that these CD11c cells co-localized with infiltrating T cells in the kidney. Using an ex- vivo co-culture system, we showed that renal-infiltrating CD11c cells promoted the survival, proliferation and interferon-γ production of renal-infiltrating CD4 T cells, suggesting a T cell-dependent mechanism by which these CD11c cells promote LN. Together, our results identify a pathogenic kidney-infiltrating CD11c cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN.

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Section: Discussionmentioning

confidence: 60%

Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Liao

Ren

Reihl

et al. 2017

Clinical and Experimental Immunology

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“…In addition to recurrent IGH SVs, multiple SVs were detected involving the IGH locus and non-canonical candidate partner genes (selected based on proximity to the translocation breakpoint) including the following: CD46 , which has a role in innate immune recognition23 and has been demonstrated to have increased expression in myeloma cell lines and primary myeloma cells particularly in association with 1q copy number gains 24

TXNDC5 , which has recently been described as a rare but recurrent translocation in myeloma and in this study was detected in a patient with a high hyperdiploid karyotype consistent with a previous report 5

…”

Section: Discussionmentioning

confidence: 99%

“…CD46 , which has a role in innate immune recognition23 and has been demonstrated to have increased expression in myeloma cell lines and primary myeloma cells particularly in association with 1q copy number gains 24…”

Section: Discussionmentioning

confidence: 99%

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

et al. 2018

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AimsMultiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre.MethodsA cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline.ResultsAt least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed.ConclusionsOur results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology.

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“…Preclinical in vitro and in vivo studies in mouse xenograft models suggest that SGN-CD325A could prove to be a viable option for treating multiple myeloma in clinical trials 73 . Antibody-drug conjugates for treating multiple myeloma have also been recently developed targeting B-cell maturation antigen (BCMA) with monomethyl auristatin F (MMAF)(GSK2857916) 74 , CD46 with MMAF 75 , and CD56 with the maytansinoid DM1 76 . While the anti-CD56 ADC, lorvotuzumab mertansine, has moved onto clinical trials (NCT00991562), the specificity towards CD46 (CD46-ADC) is the most novel myeloma antibody-drug conjugate developed recently.…”

Section: Engineered Antibodies Enzymes and Antibody-drug Conjugamentioning

confidence: 99%

“…This approach is notable because of the previously underappreciated targeting of CD46. Although, CD46 is not a surface marker required, by myeloma cells or other B-cell lineage cells, it has been shown to be upregulated in myeloma cells because of the copy number duplications on chromosome 1q, but remains unexpressed outside placenta and prostate tissues 75 . Chromosome 1q amplifications are a known marker for poor prognosis in multiple myeloma 75 , so targeting this subset of myeloma is a relatively untapped niche of myeloma research and should, therefore, be developed further.…”

Section: Engineered Antibodies Enzymes and Antibody-drug Conjugamentioning

confidence: 99%

Drug discovery and therapeutic delivery for the treatment of B and T cell tumors

Stephenson

Singh

2017

Advanced Drug Delivery Reviews

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Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure. This review aims to summarize advances in targeting lymphoma, leukemia, and myeloma in both cutting-edge and well established platforms. Current standard of treatment will be reviewed for these malignancies and emphasis will be made on new therapy development in the areas of antibody engineering, epigenetic small molecule inhibiting drugs, vaccine development, and chimeric antigen receptor cell engineering. In addition, platforms for the delivery of these and other drugs will be reviewed including antibody-drug conjugates, micro- and nanoparticles, and multimodal hydrogels. Lastly, we propose that tissue engineered constructs for hematological malignancies are the missing link in targeted drug discovery alongside mouse and patient-derived xenograft models.

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Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

Cited by 84 publications

References 60 publications

Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

Drug discovery and therapeutic delivery for the treatment of B and T cell tumors

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