CD38 as theranostic target in oncology

Abstract

CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like ⁶⁸ Ga, ⁶⁴Cu, and SPECT radionuclides like ^99mTc and ¹¹¹In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting α particles, like ²²⁵Ac, ²¹²Pb or ²¹¹At, and β^--particles like ⁹⁰Y, ¹³¹I, or ¹⁷⁷Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.

Fig. 1

Schematic representation of the CD38 distribution in human body based on data from “The Human Protein Atlas” (https://www.proteinatlas.org/ENSG00000004468-CD38). The RNA-seq data are reported as nTPM (normalized transcript expression values) for different types of human tissues. A CD38 RNA expression detected in different organs, showing a predominance in hematopoietic tissues. B CD38 expression at immune cells level, grouped by types of immune cells

Fig. 2

Distribution of CD38 glycoprotein in the human body and the cancer related to its presence. CD38 is involved in the development of various malignancies, both solid and liquid tumors, related to various organs. Created with BioRender.com

Fig. 3

Schematic representation of molecular mechanism of daratumumab combined therapy. A Dara with checkpoint inhibitors. The downregulation of the PD-L1/PD-1 pathway in MM cells, leads to the upregulation of CD38 on NK cells and their ADCC, favorizing a durable response. B Dara with IMiDs. IMiDs work by reducing IKZF1/3 levels, which increases CD38 expression, improving the effectiveness of Daratumumab treatment. NK cell-mediated ADCC is increased by enhancing both the number and activity of NK cells and reducing regulatory T cells (Tregs). Additionally, it stimulates macrophage-mediated ADCP. C Dara with PIs. The combination increases DR5 levels and decreases HLA-E levels, which strengthens NK cell-mediated ADCC and reduces immune evasion. D Dara with NK cells therapy. The tumor-killing ability of CD38low/- NK cells is improved by reducing the fratricide CD38high/- NK cells. Created by Biorender.com

Fig. 4

Different agent created targeting CD38 for treating multiple myeloma. Created with BioRender.com

Fig. 5

Visual summary of theranostic potential of anti-CD38 agents. Created with BioRender.com