Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose

Kamath, Amrita V.; Lü, Dan; Gupta, Priyanka; Jin, Denise; Xiang, Hong; Wong, Anne; Leddy, Cecilia; Crocker, Lisa; Schaefer, Gabriele; Sliwkowski, Mark X.; Damico‐Beyer, Lisa A.

doi:10.1007/s00280-011-1806-6

Cited by 36 publications

(21 citation statements)

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“…127,179 Dual-specific antibodies against HER-2:HER-3 or EGFR:HER-3 heterodimers are being evaluated but none have yet to be useful. 180,181 Our results shows that combination treatment with HER-2 and HER-3 peptide vaccine antibodies in 3 different cell lines, BT-474 breast cancer cell line, Capan-2 pancreatic and HT-29 colon cells caused an increased rate of inhibition of proliferation versus single treatments. Phosphorylated levels of HER-2 and HER-3 following combined treatment with both HER-2 and HER-3 peptide antibodies caused enhanced inhibition of phosphorylation as compared to individual treatment.…”

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confidence: 81%

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A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

Kaumaya

2015

Human Vaccines & Immunotherapeutics

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confidence: 81%

“…127,179 Dual-specific antibodies against HER-2:HER-3 or EGFR:HER-3 heterodimers are being evaluated but none have yet proven to be useful. 180,181 Overall, the results ( Table 5) point to the potential benefits of targeting HER-3 and HER-2 combinations in cancers that express these receptors. 138 …”

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confidence: 95%

A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

Kaumaya

2015

Human Vaccines & Immunotherapeutics

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“…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. BsAbs can be generated by a variety of approaches.…”

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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“…multi-cell complex including immunologic effector cells enables a broadly efficacious anti-cancer therapy. 12 As indicated by promising results derived from preclinical or early clinical studies, [13][14][15] the therapeutic application of trifunctional and bivalent antibodies such as ertumaxomab (anti-Her2, anti-CD3, Fc-region) or catumaxomab (anti-EpCAM, anti-CD3, Fc-region) antibody, 12 or bispecific antibody fusion proteins such as MM-111 (anti-Her2, anti-HER-3 single chain variable fragments) and dual-action antibodies such as MEHD7945A (anti-EGFR and anti-Her3 by each antigen binding fragment) might be superior to monospecific immunogobulins. For example, combining the advantages of targeting two different antigens with one drug might be more efficient and could significantly contribute to overcoming resistance.…”

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confidence: 99%

“…For example, combining the advantages of targeting two different antigens with one drug might be more efficient and could significantly contribute to overcoming resistance. 15 Patients benefit from dual Her2 antibody-targeting with trastuzumab plus pertuzumab (in addition to chemotherapy), [16][17][18] which is mainly due to a more effective inhibition of Her2-dependent cellular signaling compared with treatment with either antibody alone. 16,19 Although both antibodies verifiably have the capacity to elicit antibody-dependent cell-mediated cytotoxicity (ADCC), 20 their (complementary) effect has been mainly attributed to cellular effects, 21 e. g., prevention of Her2 cleavage (trastuzumab) 21 and inhibition of HER2 homo- 10 and to their fundamental role in cellular signaling, the key proteins of these pathways, ERK1/2, AKT and STAT3α/β, were analyzed.…”

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confidence: 99%

Trifunctional antibody ertumaxomab: Non-immunological effects on Her2 receptor activity and downstream signaling

Diermeier-Daucher

Ortmann²,

Buchholz³

et al. 2012

mAbs

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© 2 0 1 2 L a n d e s B i o s c i e n c e . D o n o t d i s t r i b u t e . IntroductionThe human epidermal growth factor receptor 2 (Her2) represents a prominent molecular target for trastuzumab therapy not only in breast cancer, but also in gastric, head and neck and other malignancies. 1 Clinical response rates, however, generally do not exceed a rate of ~30% (10-60%), an observation that can be reproduced in vitro.2 Although molecular mechanisms causing tumor cell resistance to treatment are manifold, modular Her2 receptor targeting using different antibodies (e.g., pertuzumab) or small molecule kinase inhibitors (e.g., lapatinib) has proven to be a successful strategy to overcome insufficient sensitivity/resistance. Alternate receptor Background: the trifunctional antibody ertumaxomab bivalently targets the human epidermal growth factor receptor 2 (Her2) on epithelial (tumor) cells and the t cell specific CD3 antigen, and its Fc region is selectively recognized by Fcγ type I/III receptor-positive immune cells. As a trifunctional immunoglobulin, ertumaxomab therefore not only targets Her2 on cancer cells, but also triggers immunological effector mechanisms mediated by t and accessory cells (e.g., macrophages, dendritic cells, natural killer cells). Whether molecular effects, however, might contribute to the cellular antitumor efficiency of ertumaxomab are largely unknown.Results: the K d of ertumaxomab for Her2-binding was determined at 265 nM and the ertumaxomab binding epitope was found to not overlap with that of the therapeutic anti-Her2 monoclonal antibodies trastuzumab and pertuzumab. ertumaxomab caused an increase in Her2 phosphorylation at higher antibody concentrations, but changed neither the rate of Her2-homodimerization /-phosphorylation nor the activation state of key downstream signaling proteins analyzed.Methods: potential molecular effects of ertumaxomab on Her2-overexpressing Bt474 and SK-BR-3 breast cancer cells were evaluated. the dissociation constant K d of ertumaxomab was calculated from titration curves that were recorded by flow cytometry. treatment-induced changes in Her2 homodimerization were determined by flow cytometric fluorescence resonance energy transfer measurements on a cell-by-cell basis. potential activation / deactivation of Her2, eRK1/2, AKt and StAt3 were analyzed by western blotting, Immunochemistry and immunofluorescent cell staining.Conclusions: the unique mode of action of ertumaxomab, which relies more on activation of immune-mediated mechanisms against tumor cells compared with currently available therapeutic antibodies for breast cancer treatment, suggests that modular or sequential treatment with the trifunctional bivalent antibody might complement the therapeutic activity of other anti-Her2/anti-erbB receptor reagents.

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Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose

Abstract: The PK of MEHD7945A was nonlinear in mouse and monkey in the dose range tested. The nonspecific clearance in monkey was approximately twofold higher than typical humanized IgG1 antibodies. The projected human efficacious dose and dose regimen appear to be achievable in patients.

Cited by 36 publications

References 15 publications

A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

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

Trifunctional antibody ertumaxomab: Non-immunological effects on Her2 receptor activity and downstream signaling

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