Crystal structure of CD38 in complex with daratumumab, a first-in-class anti-CD38 antibody drug for treating multiple myeloma

Lee, Hyun Tae; Kim, Yujin; Park, Ui Beom; Jeong, Tae Jun; Lee, Sang Hyung; Heo, Yong‐Seok

doi:10.1016/j.bbrc.2020.12.048

Cited by 17 publications

(20 citation statements)

References 24 publications

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“…MM_5191 is included as a control. j The skipping of CD38 exon 6 in MM_5034 and MM_5183 was in-frame and would delete 29 amino acids (highlighted in red), including the epitope of daratumumab (PDB structure 7DUO ) 52 . …”

Section: Resultsmentioning

confidence: 99%

“…One case exhibited a splice donor mutation, while another had a point substitution of two nucleotides upstream of the splice site. This point mutation could function as a stop-gain (R251*) but instead unexpectedly induced in-frame exon skipping and removed most of the epitopes on CD38 that interact with daratumumab 52 . These events may facilitate the evasion of MM cells from binding by daratumumab, while still retaining a major portion of the extracellular domain (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As ref. 52 pointed out, that the epitope of isatuximab is composed of residues from codons 34 to 189, thus completely unaffected by this exon skipping the event. Future structural and clinical studies should explore this direction to widen the therapeutic options for patients who relapse on daratumumab.…”

Section: Discussionmentioning

confidence: 99%

“…Additional information about the application process can be found on dbGaP website . All structures used in the analysis ( 7DUO 52 and 4CI2 46 ) are available on PDB. The remaining data are available within the Article, Supplementary Information , or Source Data file.…”

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confidence: 99%

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The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

Mishler

et al. 2022

Nat Commun

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Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease’s molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45–65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

Mishler

et al. 2022

Nat Commun

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“…Co-crystallization structures of daratumumab and isatuximab Fab fragments binding CD38 were merged by superposition of CD38 using ChimeraX 1.1 (36)(37)(38).…”

Section: Structural Analysismentioning

confidence: 99%

Identification of New Antibodies Targeting Malignant Plasma Cells for Immunotherapy by Next-Generation Sequencing-Assisted Phage Display

et al. 2022

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To identify new antibodies for the treatment of plasma cell disorders including multiple myeloma (MM), a single-chain Fragment variable (scFv) antibody library was generated by immunizing mice with patient-derived malignant plasma cells. To enrich antibodies binding myeloma antigens, phage display with cellular panning was performed. After depleting the immune library with leukocytes of healthy donors, selection of antibodies was done with L-363 plasma cell line in two consecutive panning rounds. Monitoring the antibodies’ enrichment throughout the panning by next-generation sequencing (NGS) identified several promising candidates. Initially, 41 unique scFv antibodies evolving from different B cell clones were selected. Nine of these antibodies strongly binding to myeloma cells and weakly binding to peripheral blood mononuclear cells (PBMC) were characterized. Using stably transfected Chinese hamster ovary cells expressing individual myeloma-associated antigens revealed that two antibodies bind CD38 and intercellular adhesion molecule-1 (ICAM-1), respectively, and 7 antibodies target yet unknown antigens. To evaluate the therapeutic potential of our new antibodies, in a first proof-of-concept study the CD38 binding scFv phage antibody was converted into a chimeric IgG1. Further analyses revealed that #5-CD38-IgG1 shared an overlapping epitope with daratumumab and isatuximab and had potent anti-myeloma activity comparable to the two clinically approved CD38 antibodies. These results indicate that by phage display and deep sequencing, new antibodies with therapeutic potential for MM immunotherapy can be identified.

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Development of New CD38 Targeted Peptides for Cancer Imaging

Zheleznyak,

Tang,

Duncan

et al. 2024

Mol Imaging Biol

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Purpose Multiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges. Procedures Using phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems. Results The CD38-targeted bioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 – 6.6 MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291 nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4 h. Clearance from non-target organs occurred within 60 min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4 h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1 h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4 h). Conclusions The novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

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Crystal structure of CD38 in complex with daratumumab, a first-in-class anti-CD38 antibody drug for treating multiple myeloma

Cited by 17 publications

References 24 publications

The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma

Identification of New Antibodies Targeting Malignant Plasma Cells for Immunotherapy by Next-Generation Sequencing-Assisted Phage Display

Development of New CD38 Targeted Peptides for Cancer Imaging

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