Rational engineering of antibody therapeutics targeting multiple oncogene pathways

Fitzgerald, Jonathan B.; Lugovskoy, Alexey A.

doi:10.4161/mabs.3.3.15299

Cited by 33 publications

(23 citation statements)

References 81 publications

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“…Immunoglobulins, with their typical tetrameric organization consisting of two light and two heavy polypeptide chains, are indispensable in basic research and diagnostics, as they can be adapted for the binding of an incredible variety of ligands (Chester & Hawkins, 1995;Sundberg, 2009). Bispecific antibodies that are capable of simultaneous binding to two different antigens are further improving the prospects for clinical applications of conventional antibodies (Fitzgerald & Lugovskoy, 2011). Some shortcomings of antibodies, such as their lengthy timeframe and high cost of production, and their large size can be overcome by development of small single-domain antibody fragments of high stability with the unique capacity to recognize molecules that are inaccessible to conventional antibodies (de Marco, 2011).…”

Section: Diversity Of Ligand-binding Proteinsmentioning

confidence: 99%

Ligand-Binding Proteins: Structure, Stability and Practical Application

Stepanenko¹,

Fonin²,

Stepanenko³

et al. 2012

Protein Structure

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Section: Diversity Of Ligand-binding Proteinsmentioning

confidence: 99%

Ligand-Binding Proteins: Structure, Stability and Practical Application

Stepanenko¹,

Fonin²,

Stepanenko³

et al. 2012

Protein Structure

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“…9 However, the need to inhibit multiple targets, either due to resistance or the fact that many tumors are driven by multiple growth factor pathways, has led to increased interest in the development of multispecific therapeutic agents. 10 Over 50 molcular formats have been engineered for the creation of bispecific molecules, which attests to the excitement and potential therapeutic development opportunities offered by these designs. 11,12 Among them, bispecific antibodies (BsAbs), a family of engineered antibody derivatives that recognize two different target antigens (e.g., HER2xHER3, 13 HER3xIGF-1R 14 and EGFRxHER3 15 for pathway blockage, or EpCAMxCD3 16 and CD3xCD19 17 for immune effector cell re-direction), are of particular interest.…”

Section: Introductionmentioning

confidence: 99%

“…22 For BsAbs that target two membrane bound receptors on the same cell, once one arm of the antibody is bound to the first target (R1), the second arm is restricted to a narrow region above the plasma membrane (e.g., 100 A ), and is thus concentrated near the cell surface. 10 This can result in a much faster secondary binding event to the second receptor (R2), driven by the geometric reach of a cellsurface tethered antibody (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody

Zheng

Moores

Jarantow

et al. 2016

mAbs

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Multispecific proteins, such as bispecific antibodies (BsAbs), that bind to two different ligands are becoming increasingly important therapeutic agents. Such BsAbs can exhibit markedly increased target binding and target residence time when both pharmacophores bind simultaneously to their targets. The cross-arm binding efficiency (x) describes an increase in apparent affinity when a BsAb binds to the second target or receptor (R2) following its binding to the first target or receptor (R1) on the same cell. x is an intrinsic characteristic of a BsAb mostly related to the binding epitopes on R1 and R2. x can have significant impacts on the binding to R2 for BsAbs targeting two receptors on the same cell. JNJ-61186372, a BsAb that targets epidermal growth factor receptor (EGFR) and c-Met, was used as the model compound for establishing a method to characterize x. The x for JNJ-61186372 was successfully determined via fitting of in vitro cell binding data to a ligand binding model that incorporated x. The model-derived x value was used to predict the binding of JNJ-61186372 to individual EGFR and c-Met receptors on tumor cell lines, and the results agreed well with the observed IC 50 for EGFR and c-Met phosphorylation inhibition by JNJ-61186372. Consistent with the model, JNJ-61186372 was shown to be more effective than the combination therapy of anti-EGFR and anti-c-Met monovalent antibodies at the same dose level in a mouse xenograft model. Our results showed that x is an important characteristic of BsAbs, and should be considered for rationale design of BsAbs targeting two membrane bound targets on the same cell.

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“…Adopting a different strategy, two or more ABDs can be genetically fused to a ‘stable' scaffold allowing further diversity of bispecific molecules. Examples are Fc- or IgG-based bispecific antibody molecules [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97], which have recently entered clinical trials as T-cell recruiters [98]. …”

Section: Principles Of Bispecific Antibody Engineeringmentioning

confidence: 99%

Recombinant Antibodies to Arm Cytotoxic Lymphocytes in Cancer Immunotherapy

Koch

Tesar

2017

Transfus Med Hemother

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Immunotherapy has the potential to support and expand the body's own armamentarium of immune effector functions, which have been circumvented during malignant transformation and establishment of cancer and is presently considered to be the most promising treatment option for cancer patients. Recombinant antibody technologies have led to a multitude of novel antibody formats, which are in clinical development and hold great promise for future therapies. Among these formats, bispecific antibodies are extremely versatile due to their high efficacy to recruit and activate anti-tumoral immune effector cells, their excellent safety profile, and the opportunity for use in combination with cellular therapies. This review article summarizes the latest developments in cancer immunotherapy using immuno-engagers for recruiting T cells and NK cells to the tumor site. In addition to antibody formats, malignant cell targets, and immune cell targets, opportunities for combination therapies, including check point inhibitors, cytokines and adoptive transfer of immune cells, will be summarized and discussed.

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Rational engineering of antibody therapeutics targeting multiple oncogene pathways

Cited by 33 publications

References 81 publications

Ligand-Binding Proteins: Structure, Stability and Practical Application

Ligand-Binding Proteins: Structure, Stability and Practical Application

Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody

Recombinant Antibodies to Arm Cytotoxic Lymphocytes in Cancer Immunotherapy

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