Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

Abstract

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.

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

“…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.…”

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing

“…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

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“…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…”

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

“…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.…”

“…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.…”