A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies

Heider, Karl-Heinz; Kiefer, Kerstin; Zenz, Thorsten; Volden, Matthias; Stilgenbauer, Stephan; Ostermann, Elínborg; Baum, Anke; Lamche, Herbert R.; Küpcü, Zaruhi; Jacobi, Alexander; Müller, Susanne; Hirt, Ulrich; Adolf, Günther R.; Borges, Eric

doi:10.1182/blood-2011-04-351932

Cited by 99 publications

(85 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CD37 has recently attracted interest as a target for monoclonal antibodies with therapeutic potential in B-cell malignancies [7,8]. However, most of what is known about the contribution of CD37 to immunology has been gleaned from CD37…”

Section: Introductionmentioning

confidence: 99%

“…The cellular processes regulated by tetraspanin-mediated molecular organization include proliferation, adhesion and migration [2,3]. In immune cells, many important cell surface molecules, such as integrins, co-receptors, pattern recognition receptors and MHC molecules, are incorporated into tetraspanin-enriched microdomains [4][5][6].CD37 has recently attracted interest as a target for monoclonal antibodies with therapeutic potential in B-cell malignancies [7,8]. However, most of what is known about the contribution of CD37 to immunology has been gleaned from CD37…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

et al. 2013

View full text Add to dashboard Cite

Previous studies on the role of the tetraspanin CD37 in cellular immunity appear contradictory. In vitro approaches indicate a negative regulatory role, whereas in vivo studies suggest that CD37 is necessary for optimal cellular responses. To resolve this discrepancy, we studied the adaptive cellular immune responses of CD37 −/− mice to intradermal challenge with either tumors or model antigens and found that CD37 is essential for optimal cell-mediated immunity. We provide evidence that an increased susceptibility to tumors observed in CD37 −/− mice coincides with a striking failure to induce antigenspecific IFN-γ-secreting T cells. We also show that CD37 ablation impairs several aspects of DC function including: in vivo migration from skin to draining lymph nodes; chemotactic migration; integrin-mediated adhesion under flow; the ability to spread and form actin protrusions and in vivo priming of adoptively transferred naïve T cells. In addition, multiphoton microscopy-based assessment of dermal DC migration demonstrated a reduced rate of migration and increased randomness of DC migration in CD37 −/− mice.Together, these studies are consistent with a model in which the cellular defect that underlies poor cellular immune induction in CD37 −/− mice is impaired DC migration. Keywords: CD37 r Cellular immunity r Dendritic cells r Migration r TetraspaninsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdaptive cellular immunity is initiated by presentation of foreign antigen by DCs to antigen-specific naïve T lymphocytes. DCs exist sparsely in peripheral tissues in a state specialized for antigen uptake and processing. However, upon pathogen encounter, DCsCorrespondence: Dr. Mark D. Wright e-mail: Mark.Wright@monash.edu transduce signals through pattern recognition receptors, leading to an increased expression of cell surface molecules and cytokines, and induction of DC migration from the periphery to draining lymph nodes (DLNs) via afferent lymphatic vessels. Thus, upon their arrival in secondary lymphoid organs, DCs are equipped to initiate adaptive cellular immune responses through their ability to * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1208-1219 Cellular immune response 1209 activate naïve antigen-specific T cells [1]. Despite the importance of DC migration from the periphery to DLNs, the roles of the numerous molecules that regulate this process are incompletely understood. One such molecule is the leukocyte-specific membrane protein CD37, a member of the tetraspanin protein superfamily. Tetraspanins molecularly organize cellular membranes by interactions with partner molecules, which they direct into regulated signal-transducing tetraspanin-enriched microdomains. The cellular processes regulated by tetraspanin-mediated molecular organization include proliferation, adhesion and migration [2,3]. In immune cells, many important cell s...

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In B cells, the actions of CD37 contribute to development of humoral immunity (9)(10)(11). Moreover, CD37 is a target for novel immunotherapies to treat B cell malignancies (12)(13)(14)(15)(16)(17)(18). CD37 has also been shown to control functions in T cells and dendritic cells (19)(20)(21)(22).…”

mentioning

confidence: 99%

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Wee

Schulze

Jones

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin–dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1–adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

show abstract

“…Similarly, in humans, non-linear PK has been observed after the administration of CD33-targeted therapies 40 41 , 44 , 52-54 Characterization of the target sink that may be driving the non-linear PK usually requires concentration-time profiles obtained over a range of administered doses. In the case of an ADC bearing a cytotoxic payload, the feasible dose range for a PK study may be limited by the drug's overall tolerability in animals and the sensitivity of the analytical methods.…”

Section: Discussionmentioning

confidence: 99%

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Figueroa

Leipold

Leong

et al. 2018

mAbs

View full text Add to dashboard Cite

For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

show abstract

A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies

Abstract: The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human

Cited by 99 publications

References 30 publications

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Contact Info

Product

Resources

About