CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

Abstract

CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule and has been implicated in malignant B-cell proliferation and survival.These biological functions combined with expression of CD74 on malignant B cells and limited expression on normal tissues implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody LL1 has been humanized (hLL1milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies, particularly because this antibody shows rapid internalization into CD74 + malignant cells. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. These studies show that unconjugated hLL1and conjugates of hLL1constructs with radioisotopes, doxorubicin, and frog RNase have high antitumor activity innon^Hodgkin's lymphoma and multiple myeloma invitro andin tumor xenograft models. Singledose studies of hLL1 in monkeys showed no adverse effects but did decrease circulating B and T lymphocytes and natural killer cells. When evaluated in combination with rituximab, either equivalent or improved efficacy, compared with either antibody alone, was observed. CD74 is a new candidate target for the immunotherapy of neoplasms expressing this antigen, which can be exploited using either a naked antibody or conjugated to isotopes, drugs, or toxins. CD74 (invariant chain, Ii) is a type II transmembraneglycoprotein that associates with the MHC class II a and h chains and directs the transport of the ahIi (invariant chain) complexes to endosomes and lysosomes (1 -4). In addition, CD74 is involved in signaling pathway functioning as a survival receptor (5). These biological functions, combined with expression of CD74 on malignant B cells and limited expression on normal tissues, implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody (mAb) LL1 has been humanized (hLL1 milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. The evidence suggests that hLL1 is a promising candidate antibody for the therapy of CD74-expressing malignancies, such as non -Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Due to its rapid internalization property, hLL1 also shows considerable promise as a drug, isotope, or toxin immunoconjugate. CD74 Molecule: Structure, Function, and ExpressionCD74 has 30 NH 2 -terminal, intracytoplasmic amino acid residues, a 26-amino acid hydrophobic transmembrane region, and a 160-amino acid extracytoplasmic domain containing two N-linked carbohydrate chains (1, 6). Once synthesized, CD74, DRa, and DRh begin to associate within the endoplasmic reticulum. This is believed to occur by sequential addition of DRa/h heterodimers to a trimeric core of CD74 molecules until a nine-subunit...

Macrophage Migration Inhibitory Factor: a Potential Marker for Cancer Diagnosis and Therapy

“…Also ISO-1 and other small inhibitory molecules of MIF are being developed and tested in cancers with higher MIF levels. A humanized antibody developed against MIF's receptor is in clinical trials for lymphoproliferative disorders (Stein et al, 2007;Bifulco et al, 2008). In silico studies can also prove to be helpful in finding new targets for MIF.…”

Investigational Immunotherapeutics for B-Cell Malignancies

“…65 Milatuzumab (hLL1, IMMU-115), an anti-CD74 mAb, does not cause direct cytotoxicity in vitro; in the presence of an appropriate cross-linking agent, this antibody induces inhibition of cell proliferation and apoptosis but very modest ADCC or CDC. 66 In vivo, milatuzumab therapy resulted in significant prolongation of survival in SCID mice using the human Burkitt's, Daudi, and Raji lymphoma cell lines. 67 Phase I trials of milatuzumab in B-cell NHL and CLL are underway.…”

Immunotherapy for B-Cell Neoplasms Using T-Cells Expressing Chimeric Antigen Receptors : From Antigen Choice to Clinical Implementation

“…Under the inflammatory processes, CD74 is also detected in high levels on endothelial and epithelial cells as well as on a variety of malignant cells. 45 Its overexpression is observed in several forms of cancer and many B-cell neoplasms, including non-Hodgkin lymphoma, chronic lymphocytic leukaemia, multiple myeloma, and follicular lymphoma. In many of these cancers, increased CD74 expression is associated with tumour progression and poor clinical outcomes.…”

“…In many of these cancers, increased CD74 expression is associated with tumour progression and poor clinical outcomes. 45 Compared to normal tissue, the relatively high expression of CD74 combined with the rapid internalisation of CD74 on ligation makes it an attractive target for CAR design.…”