Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody

Wang, Yan; Pan, Donghui; Huang, Chenrong; Chen, Bingliang; Li, Mingzhu; Zhou, Shuaixiang; Wang, Lizhen; Wu, Min; Wang, Xinyu; Bian, Yicong; Yan, Junjie; Liu, Junjian; Yang, Min; Miao, Liyan

doi:10.1080/19420862.2020.1748322

Cited by 28 publications

(19 citation statements)

References 32 publications

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“…Meanwhile, dose selection for first-in-class human (FIH) studies of IBI322, authorized by the National Medical Products Administration (NMPA) for clinical trials (IND No. CXSL1900125) was evaluated, suggesting that the preliminary pharmacodynamics (PD) study with 0.34 mg/kg was rational ( 46 ). For scientific confirmation, it still needs more researches at different doses to be conducted in future.…”

Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Yang

2021

Front. Immunol.

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The prosperity of immunological therapy for cancer has aroused enormous passion for exploiting the novel targets of cancer immunotherapy. After the approval of blinatumomab, a bispecific antibody (bsAb) targeting on CD19 for acute lymphoblastic leukemia, a few of CD47-targeted bsAbs for cancer immunotherapy, are currently in clinical research. In our review of CD47-targeted bsAbs, we described the fundamental of bsAbs. Then, we summarized the information of four undergoing phase I researches, reviewed the main toxicities relevant to CD47-targeted bsAb immunological therapy of on-target cytotoxicity to healthy cells and a remarkable antigen-sink. Finally, we described possible mechanisms of resistance to CD47-targeted bsAb therapy. More clinical researches are supposed to adequately confirm its security and efficacy in clinical practice.

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Section: Bsab Targeting Cd47 and Other Targets That Are Currently In Clinical Trials In Oncologymentioning

confidence: 99%

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Yang

2021

Front. Immunol.

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“…by targeting CD19), this is not necessarily the case for targeting TAA expressed on solid tumors and associated healthy tissues. IBI322 is a CD47 × PDL-1 BsAb developed by Innovent Biologics which preferentially accumulated in PD-L1 positive solid tumors, thereby reducing the potential side effects due to the CD47 pathway blockade in healthy cells (Wang et al 2020 ). In another example, RO6874813 is a 2:2 CrossMab that binds with high to fibroblast activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and low affinity to death receptor 5 (DR5).…”

Section: Increased Tumor Selectivitymentioning

confidence: 99%

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Huang

Duijnhoven²,

Sijts

et al. 2020

J Cancer Res Clin Oncol

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Purpose Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. Methods Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. Results Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. Conclusions Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.

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“…Referring to the previous study, 29 the tumour uptake of 89 Zr PET imaging consists of two parts: one was the specific part, which related to the cumulative exposure of 89 Zr‐CAR T cells over time; and the other was the non‐specific part, which associated with the plasma concentration (Cp). The Patlak model:

normalTumour normaluptake (% ID false/ normalg) = A * Cp (normalt) + B * \int_{0}^{normalt} Cp (normalτ) normald τ

can be used to quantify the specific and non‐specific parts.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic studies of CD19 CAR T cell in human leukaemic xenograft models with dual‐modality imaging

Wang

et al. 2021

J Cellular Molecular Medi

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In recent years, chimeric antigen receptor T (CAR T)‐cell therapy has shown great potential in treating haematologic disease, but no breakthrough has been achieved in solid tumours. In order to clarify the antitumour mechanism of CAR T cell in solid tumours, the pharmacokinetic (PK) and pharmacodynamic (PD) investigations of CD19 CAR T cell were performed in human leukaemic xenograft mouse models. For PK investigation, we radiolabelled CD19 CAR T cell with 89Zr and used PET imaging in the CD19‐positive and the CD19‐negative K562‐luc animal models. For PD evaluation, optical imaging, tumour volume measurement and DNA copy‐number detection were performed. Unfortunately, the qPCR results of the DNA copy number in the blood were below the detection limit. The tumour‐specific uptake was higher in the CD19‐positive model than in the CD19‐negative model, and this was consistent with the PD results. The preliminary PK and PD studies of CD19 CAR T cell in solid tumours are instructive. Considering the less efficiency of CAR T‐cell therapy of solid tumours with the limited number of CAR T cells entering the interior of solid tumours, this study is suggestive for the subsequent CAR T‐cell design and evaluation of solid tumour therapy.

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Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody

Cited by 28 publications

References 32 publications

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Pharmacokinetic and pharmacodynamic studies of CD19 CAR T cell in human leukaemic xenograft models with dual‐modality imaging

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