CD37 is a tetraspanin family plasma membrane protein involved in cell membrane organization and cosignaling. CD37 is selectively expressed on mature B cells and has limited or no expression on other hematopoietic cells such as T cells and NK cells, granulocytes, monocytes and dendritic cells. CD37 is present on the cell surface, but also on endosomes and exosomes, which contributes to intracellular trafficking and immunomodulation.1-3

The biologic function of CD37 is not yet fully elucidated, however recent advances suggest the protein plays a role in pro-survival and pro-apoptotic signaling via the PI3K/AKT pathway. In addition, it controls IL-6 receptor signaling through interaction with SOCS3. 1,2

  • CD37 can mediate the clustering of α4β1 integrins, which is followed by activation of PI3K/AKT signaling and cell survival.
  • However, CD37 can also create a complex with SHP1, LYN, SYK, and PI3Kγ, leading to AKT inactivation, and recruit SOCS3, limiting the IL6/STAT3 loop.


On the basis of an expression pattern largely overlapping CD20, CD37 was one of the first proteins explored as therapeutic target in non-Hodgkin lymphomas in the late 1980s and a renewed interest in this target has supported the development of new therapeutic agents targeting CD37.2

  • Interestingly, CD37 antibody-based therapeutics currently in (pre-)clinical development are poor inducers of complement-dependent cytotoxicity (CDC), another powerful Fc-mediated effector mechanism for killing hematological cancer cells.1
  • Activation of the classical complement pathway by IgG antibodies depends on IgG hexamer formation upon binding to membrane bound antigens, while the introduction of a single point mutation in the IgG Fc domain increases IgG hexamer formation and enhances CDC activity.1
  • Therefore, locally increasing the density of Fc-domains through dual epitope targeting can potentiate CDC and may also favorably affect Fc-mediated antibody hexamerization.1

In preclinical settings, dual-epitope bispecific DuoHexaBody®-CD37 has been shown to induce potent in vivo and in vitro anti-tumor activity.1

Oncogenic Expression

  • In cancer, CD37 is highly expressed on malignant B cells in a variety of B-cell lymphomas and leukemias, including NHL and CLL.1-3
  1. Oostindie SC, et al. DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies. Blood Cancer Journal. 2020;10:30.
  2. Bertoni F, et al. Staining the target: CD37 expression in lymphomas. Blood. 2016;128(26).
  3. Zhao X, et al. Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical. Blood. 2007;110(7):2569-2577.

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