Beyond bispecificity: Controlled Fab arm exchange for the generation of antibodies with multiple specificities

Yanakieva, Desislava; Pekar, Lukas; Evers, Andreas; Markus, Fleischer; Keller, Stephan Sylvest; Mueller-Pompalla, Dirk; Kolmar, Harald; Zielonka, Stefan; Krah, Simon

doi:10.1080/19420862.2021.2018960

Cited by 26 publications

(16 citation statements)

References 45 publications

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“…This strategy involved immunization of camelids followed by YSD‐based antibody selection. sdAbs such as camelid‐derived VHH domains afford the benefit of multiple reformatting options owing to their simple structure and composition compared to canonical paratopes (Könning et al, 2017; Krah et al, 2016; Pekar et al, 2020; Yanakieva et al, 2022). Moreover, sdAbs can be readily obtained using different display technologies (Pardon et al, 2014; Roth et al, 2020; Sellmann et al, 2020; Valldorf et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

et al. 2023

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Herein, we describe the generation of potent NK cell engagers (NKCEs) based on single domain antibodies (sdAbs) specific for NKp46 harboring the humanized Fab version of Cetuximab for tumor targeting. After immunization of camelids, a plethora of different VHH domains were retrieved by yeast surface display. Upon reformatting into Fc effector-silenced NKCEs targeting NKp46 and EGFR in a strictly monovalent fashion, the resulting bispecific antibodies elicited potent NK cell-mediated killing of EGFR-overexpressing tumor cells with potencies (EC 50 killing) in the picomolar range. This was further augmented via co-engagement of Fcγ receptor IIIa (FcγRIIIa). Importantly, NKp46-specific sdAbs enabled the construction of various NKCE formats with different geometries and valencies which displayed favorable biophysical and biochemical properties without further optimization. By this means, killing capacities were further improved significantly. Hence, NKp46-specific sdAbs are versatile building blocks for the construction of different NKCE formats.

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Section: Discussionmentioning

confidence: 99%

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

et al. 2023

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“…The generation of engineered molecules, combining arms specific for different NK receptors and targeting tumor epitopes, represents an important element for the assembly of new therapeutic strategies. These multivalent molecules (bi- tri- or tetra-specific engagers) [ 101 , 102 , 103 , 104 ] may combine multiple therapeutic effects, depending on the assembled specificities, stimulating triggering NK receptors and cytokine receptors, blocking ICs, and targeting tumor cells. Another important approach deals with the use of combined cytokine cocktails (IL-12, IL-18, IL-15) to get the so-called Cytokine-Induced Memory-Like (CIML) NK cells.…”

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy

Grottoli

Carrega

Zullo

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs) immunotherapy has represented a breakthrough in cancer treatment. Clinical use of ICIs has shown an acceptable safety profile and promising antitumor activity. Nevertheless, some patients do not obtain clinical benefits after ICIs therapy. In order to improve and cure an increasing number of patients, the field has moved toward the discovery of new ICIs expressed by cells of innate immunity with an elevated inherent antitumor activity, such as natural killer cells. This review will focus on the recent findings concerning the role of classical and non-classical immune checkpoint molecules and receptors that regulate natural killer cell function, as potential targets, and their future clinical application.

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“…Tetraspecific NKCEs also come in different formats. The DuoBody (DB)-VHH incorporates VHH with different specificities attached to the heavy chain C-terminal ends of a bispecific, Fc-silent IgG 58 . One or two VHH against EGFR, IL6R or NKG2D were appended to a HER2/cMET BsAb.…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy

Tapia-Galisteo¹,

Compte²,

Álvarez‐Vallina³

et al. 2023

Theranostics

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Despite the clinical success of the first bispecific antibody approved by the FDA against B cell malignancies (blinatumomab), many obstacles remain such as dosing, treatment resistance, and modest efficacy in solid tumors. To overcome these limitations, considerable efforts have been dedicated to the development of multispecific antibodies, opening up new avenues to address both the complex biology of cancer and the onset of anti-tumoral immune responses. Simultaneous targeting of two tumor-associated antigens is presumed to enhance cancer cell selectivity and reduce immune escape. Co-engagement of CD3, along with agonists of co-stimulatory molecules or antagonists of co-inhibitory immune checkpoint receptors in a single molecule, may revert T cell exhaustion. Similarly, targeting of two activating receptors in NK cells may improve their cytotoxic potency. And these are only examples of the potential of antibody-based molecular entities engaging three (or more) relevant targets. From the perspective of health care costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies. Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.

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Beyond bispecificity: Controlled Fab arm exchange for the generation of antibodies with multiple specificities

Cited by 26 publications

References 45 publications

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy

When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy

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