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The multi-faceted potential of CD38 antibody targeting in multiple myeloma

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Abstract

CD38, an adenine dinucleotide phosphate (ADP) ribose cyclase and a cyclic ADP ribose hydrolase, is widely expressed on the surface of multiple myeloma (MM) cells. It is known to play a pivotal role in the downstream pathways that mediate MM cell growth, signal transduction, and adhesion. The clinical use of CD38 monoclonal antibodies (MoAbs), such as daratumumab, either as monotherapy or in combination with other anti-MM agents, has produced impressive results in patients who have failed standard MM therapy. CD38 MoAbs exhibit several cytotoxic mechanisms on MM cells. In addition to the classical effector mechanisms associated with antibody therapy, CD38 MoAbs induce MM apoptosis and clonal T-cell expansion. Here, we summarize the results of some pivotal clinical studies using a human CD38 MoAb, daratumumab, in patients with MM, discuss the anti-MM effector mechanisms induced by CD38 MoAbs, and review the potential tumor antigens that may be suitable targets for immunotherapy of MM. Finally, we present a paradigm of immunotherapy for MM patients using CD38 MoAbs followed by GM-CSF and an immune checkpoint inhibitor in patients who have undergone high dose chemotherapy and autologous stem cell transplant. CD38 MoAbs have emerged as a novel and ultimately very promising immunotherapeutic agent for MM because of its ability to induce MM cytotoxicity through both arms of the adaptive immune responses.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

ADCP:

Antibody-dependent cellular phagocytosis

ADP:

Adenine dinucleotide phosphate

ADPR:

Adenine dinucleotide phosphate ribose

APC:

Antigen presenting cell

cADPR:

Cyclic adenine dinucleotide phosphate ribose

CDC:

Complement-dependent cytotoxicity

CDR:

Complementarity determining region

CTA:

Cancer-testis antigen

DC:

Dendritic cell

FcγR:

Fcγ receptor

FDA:

Food and drug administration

GM-CSF:

Granulocyte–macrophage colony stimulating factor

HLA:

Human leukocyte antigen

Id:

Idiotypic protein

MDSC:

Myeloid-derived suppressor cell

MM:

Multiple myeloma

MoAb:

Monoclonal antibody

NAADP:

Nicotinic acid adenine dinucleotide phosphate

NAD:

Nicotinamide adenine dinucleotide

NK:

Natural killer

PD1:

Programmed death 1

PD-L1:

Programmed death ligand 1

PFS:

Progression-free survival

PR:

Partial response

Rd:

Lenalidomide and dexamethasone

SCT:

Stem cell transplant

Treg :

T regulatory

Vd:

Bortizomib and dexamethasone

VH:

Variable region of the immunoglobulin heavy chain

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  1. Division of Hematology and Oncology, Rhode Island Hospital/Brown University Warren Alpert Medical School, Room 140, APC Building, 593 Eddy Street, Providence, RI, 02903, USA

    Rory M. Shallis, Christopher M. Terry & Seah H. Lim

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  1. Rory M. Shallis
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  3. Seah H. Lim
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Shallis, R.M., Terry, C.M. & Lim, S.H. The multi-faceted potential of CD38 antibody targeting in multiple myeloma. Cancer Immunol Immunother 66, 697–703 (2017). https://doi.org/10.1007/s00262-017-1990-2

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