Dr. D. (Dubravka) Drabek

The Harbour Antibody team:

Group members (lab Ee-1002):
Rien van Haperen (research assistent)
Rick Janssens (research assistent)
Lars Koeken (technician)
Michael van der Reijden (technician)
Mieke Veltman (technician)

The Harbour Antibody team works on the generation and improvement of genetically modified mice that generate human antibodies: conventional H2L2 antibodies (containing two heavy and two light chains) and Heavy Chain Only Antibodies (HCAb).  Immunization of these mice with therapeutically relevant antigens yields fully human antibodies for therapeutic or diagnostic use primarily for anti-cancer therapies, https://harbourantibodies.com/

The Harbour  team is part of Harbour Biomed (http://www.harbourbiomed.com) and is focused on antibody platform innovations within the Department of Cell Biology. In addition the group is involved in a number of projects with collaborations outside the Erasmus MC. Current collaborative projects are:

-NCOH-LCH consortium and ACZI IN-ATAC (working on corona and influenza virus antibodies).

-GENOMETRACK a project of the Building blocks of life (NWO), see Kerstin Wendt (Cell Biology) projects.

-HAVA, an anti-snake venom project with VU Amsterdam/Leiden Naturalis/Liverpool school of Tropical Medicine

Contact e-mail address: d.drabek@erasmusmc.nl

Background

Camelids contain, in addition to conventional antibodies, functional heavy chain only antibodies (HCAbs) These are coded for by a distinct set of VH segments. Antigen binding for single chain antibodies is different from that seen with conventional antibodies, but high affinity is achieved the same way, i.e. through hypermutation of the variable region and selection of cells expressing such high affinity antibodies (affinity maturation). HCAbs  are missing the entire CH1 domain of the constant region of the heavy chain due to the loss of a functional splice acceptor sequence at the 5'side of the CH1 exon. They also possess conserved hydrophilic amino acid substitutions in the region involved in hydrophobic interaction with the light chain in conventional antibodies. The simple structure of the variable domain of camelid heavy chain immunoglobulins turned out to overcome the folding and aggregation problems of conventional antibodies. Camelid VHHs have been shown to be superior to conventional antibodies in many different aspects. They are attractive as diagnostic  and therapeutic tools based on their size, solubility and high affinities. Since mouse is smaller, easier to keep than any of the camelids and more practical animal for immunization, we have generated  initially a transgenic mouse containing  "llamelized" human heavy chain immunoglobulin locus  followed by  a series of transgenic mice containing fully human variable regions that are able to produce functional, soluble, high affinity, fully human HCAbs. While camelid variable region might cause an undesirable immune reaction when used  in human,  human VHs present a safer therapeutic option. The ease of engineering them into multi-specific agents, makes them extremely attractive from therapeutic point of view.

Conventional H2L2 antibodies on the other hand, have a long history in human therapy. Initially, first antibodies were of mouse origin, next generation were mouse/ human chimeric antibodies (where Fc region of mouse was replaced by human), followed by humanized antibodies  (where human scaffolds were used to graft CDR variable lops). To eliminate any immunological side effects, fully human antibodies are paramount  for therapy.  The best available source of fully human antibodies today (apart from limited use of human blood), are genetically modified rodents expressing human immunoglobulins. In addition to HCAb platform, Harbour team works also with the transgenic H2L2 mouse platform.

Relevant publications

Laventie BJ, Rademaker HJ, Saleh M, de Boer E, Janssens R, Bourcier T, Subilia A, Marcellin L, van Haperen R, Lebbink JH, Chen T, Prévost G, Grosveld F, Drabek D. Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins.Proc Natl Acad Sci U S A. 2011 ; 27:108(39):16404-9.

Drabek D, Janssens R, de Boer E, Rademaker R, Kloess J, Skehel J, Grosveld F. Expression Cloning and Production of Human Heavy-Chain-Only Antibodies from Murine Transgenic Plasma Cells. Front Immunol. 2016 Dec 19;7:619. doi: 10.3389/fimmu.2016. eCollection 2016

Stalin Raj V, Okba NMA, Gutierrez-Alvarez J, Drabek D, van Dieren B, Widagdo W, Lamers MM, Widjaja I, Fernandez-Delgado R, Sola I, Bensaid A, Koopmans MP, Segalés J, Osterhaus ADME, Bosch BJ, Enjuanes L, Haagmans BL. Chimeric camel/human heavy-chain antibodies protect against MERS-CoV infection. Sci Adv. 2018 Aug 8;4(8):eaas9667. doi: 10.1126/sciadv.aas9667. eCollection 2018

Widjaja I, Wang C, van Haperen R, Gutiérrez-Álvarez J, van Dieren B, Okba NMA, Raj VS, Li W, Fernandez-Delgado R, Grosveld F, van Kuppeveld FJM, Haagmans BL, Enjuanes L, Drabek D, Bosch BJ. Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein. Emerg Microbes Infect. 2019;8(1):516-530. doi: 10.1080/22221751.2019.1597644.

Wang C, Li W, Drabek D et al. A monoclonal antibody blocking SARS-Cov2 infection. Nat Commun. 2020 May 4;11(1):2251. doi: 10.1038/s41467-020-16256-y.

Drabek D, Janssens R, van Haperen R, Grosveld F. A transgenic Heaavy chain IgG mouse platform as a source of High Affinity Fully Human Single-Domain antibodies for Therapeutic Application. Methods Mol Biol 2022;2446:121-141. doi: 10.1007/978-1-0716-2075-5_6.