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Review ArticleReview

Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Brandon M. Bordeau and Joseph P. Balthasar
Cancer Biology & Medicine August 2021, 18 (3) 649-664; DOI: https://doi.org/10.20892/j.issn.2095-3941.2020.0704
Brandon M. Bordeau
1Department of Pharmaceutical Science, University at Buffalo, Buffalo, NY 14214, USA
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Joseph P. Balthasar
1Department of Pharmaceutical Science, University at Buffalo, Buffalo, NY 14214, USA
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    Figure 1

    Shown is a graphic representation of barriers that limit therapeutic antibody uptake and distribution into solid tumors and the approaches that have been reported to mitigate the tumor barriers. A graphic key is provided in the bottom left inset. Figure 1 was created using BioRender.com.

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    Table 1

    FDA approved mAbs for solid tumor indications

    Antibody (mAb)FormatIndicationTargetYear approvedTrialTrial armComparatorNotes
    Trastuzumab (Herceptin)Humanized IgG1 mAbBreast cancerHER21998mAb + chemotherapy vs. chemotherapyMTP: 7.2 months
    ORR: 45%
    DOR: 8.3 months
    1-year survival: 79%
    MTP: 4.5 months
    ORR: 29%
    DOR: 5.8 months
    1-year survival: 68%
    Approved in combination with paclitaxel for patients without prior chemotherapy or as a single agent in patients who have progressed on chemotherapy
    Cetuximab (Erbitux)Chimeric IgG1 mAbColorectal cancerEGFR2004mAb + irinotecan vs. mAbORR: 22.9%
    MTP: 4.1 months
    ORR: 10.8%
    MTP: 1.5 months
    Assessed in patients who progressed on irinotecan. Approved in combination with irinotecan for patient’s refractory to irinotecan or as a single agent for patients intolerant to irinotecan
    Bevacizumab (Avastin)Humanized IgG1Colorectal cancerVEGF2004mAb + IFL vs. IFL + placeboMTP: 20.3 months
    PFS: 10.6 months
    ORR: 45%
    DOR: 10.4 months
    MTP: 15.6 months
    PFS: 6.4 months
    ORR: 35%
    DOR: 7.1 months
    Tested in combination with 5-fluorouracil, irinotecan, leucovorin
    Panitumumab (Vectibix)Humanized IgG2 mAbColorectal cancerEGFR2006mAb + best supportive care vs. best supportive carePFS: 96 days
    ORR: 8%
    PFS: 60 days
    ORR: 0%
    Assessed in patients who progressed on fluoropyrimidine, oxaliplatin, and irinotecan. No difference in overall survival observed
    Pertuzumab (Perjeta)Humanized IgG1Breast cancerHER22012mAb + trastuzumb + docetaxel vs. placebo + trastuzumab + docetaxelPFS: 18.5 months
    ORR: 80.2%
    DOR: 20.2 months
    Survival: 82.8%
    PFS: 12.4 months
    ORR: 69.3%
    DOR: 12.5 months
    Survival: 76.4%
    Approved in combination with trastuzumab and docetaxel for patients who have not received prior therapy
    Ado-trastuzumab emtansine (Kadcyla)Humanized IgG1 ADCBreast cancerHER22012ADC vs. lapatinib + capecitabinePFS: 9.6 months
    ORR: 43.6%
    DOR: 12.6 months
    MS: 30.9 months
    PFS: 6.4 months
    ORR: 30.8%
    DOR: 6.5 months
    MS: 25.1 months
    Tested in patients with metastatic or locally advanced breast cancer with prior trastuzumab or prior taxane therapy
    Ramucirumab (Cyramza)Human IgG1Gastric cancerVEGFR22014mAb + best supportive care vs. best supportive care + placeboPFS: 2.1 months
    MS: 5.2 months
    PFS: 1.3 months
    MS: 3.8 months
    Tested in patients with locally advanced or metastatic gastric cancer who previously received platinum or fluoropyrimidine chemo
    Nivolumab (Opdivo)Human IgG4Melanoma/NSCLCPD12014Single-arm trialORR: 32%N/ATested in patients with unresectable or metastatic melanoma that progressed on ipilimumab
    Pembrolizumab (Keytruda)Humanized IgG4MelanomaPD12014Single-arm trialORR: 24%N/ATested in patients with unresectable or metastatic melanoma that progressed on ipilimumab
    Necitumumab (Portrazza)Human IgG1NSCLCEGFR2015mAb + gemcitabine + cisplatin vs. gemcitabine + cisplatinPFS: 5.7 months
    OS: 23%ORR: 31%
    MS: 11.5 months
    PFS: 5.5 months
    OS: 19%ORR: 29%
    MS: 9.9 months
    Tested as a first line chemotherapy in patients with metastatic squamous NSCLC
    Dinutuximab (Unituxin)Chimeric IgG1NeuroblastomaGD22015mAb + RA vs. RAOS: 73%
    EFS: 71%
    OS: 58%
    EFS: 56%
    Tested in pediatric patients with high risk neuroblastoma. “RA = 13-cis-retinoic acid”
    Olaratumab (Lartruvo)Human IgG1Soft tissue sarcomaPDGFR-alpha2016mAb + doxorubicin vs. doxorubicinOS: 41%
    MS: 26.5 months
    PFS: 8.2 months
    ORR: 18.2%
    OS: 22%
    MS: 14.7 months
    PFS: 4.4 months
    ORR: 7.5%
    Eligible patients were required to have soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy, a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate but had not been administered
    Atezolizumab (Tecentriq)Humanized IgG1Bladder cancerPD-L12016Single-arm trialORR: 14.8%N/ATested in patients with locally advanced or metastatic urothelial carcinoma that progressed on platinum containing chemotherapy.
    Avelumab (Bavencio)Human IgG1Merkel cell carcinomaPD-L12017Single-arm trialORR: 33%N/ATested in patients who progressed on chemotherapy for distant metastatic disease
    Durvalumab (IMFINZI)Human IgG1Bladder cancerPD-L12017Single-arm trialORR: 17%N/ATested in patients with metastatic urothelial cancer that progressed on or after a platinum-based therapy
    Cemiplimab (Libtayo)Human mAbCutaneous squamous cell carcinomaPD-12018Single-arm trialORR: 47.2%N/ATested in patients with metastatic or locally advanced CSCC that were not candidates for curative surgery or radiation
    Enfortumab vedotin (Padcev)Human IgG1 ADCUrothelial cancerNectin-42019Single-arm trialORR: 44%
    DOR: 7.6 months
    N/ATested in patients with locally advanced or metastatic urothelial cancer with prior PD-1 or platinum-based chemo
    [fam-]trastuzumab deruxtecan-nxki (Enhertu)Humanized IgG1 ADCMetastatic breast cancerHER22019Single-arm trialORR: 60.3%
    DOR: 14.8 M
    N/ATested in patients with HER2-positive, unresectable and/or metastatic breast cancer who had received 2 or more prior anti-HER2 therapies
    Sacituzumab govitecan-hziy (Trodelvy)Humanized IgG1 ADCTriple-neg. breast cancerTROP-22020Single-arm trialORR: 33.3%
    DOR: 7.7 M
    N/ATested in patients with metastatic triple negative breast cancer who progressed on 2 prior treatments.

    mAb, antibody; ADC, antibody drug conjugate; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; MS, median survival; DOR, median duration of response; EFS, event-free survival.

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      Table 2

      Vasculature modulation approaches

      TreatmentImpact on tumorImpact on mAb tumor PKmAb/tumor modelSource
      BevacizumabDecrease in tumor vasculature and permeability63% decrease in AUC (0–10 days)T84.66
      LS174T
      28
      SorafenibDecrease in tumor vasculature and permeability41% decrease in AUC (0–7 days)T84.66
      LS174T
      131
      Angiotensin IIIncrease in trans vascular pressure gradient, enhanced tumor blood flow40% increase in uptake 4 h after administrationCC49
      LS174T
      41
      TNF-alpha administered intravenously (IV) or intra-tumorally (IT)Enhanced vasopermeability(IT) 200% increase at 3 h, 27% increase at 22 h
      (IV) 100% increase at 3 h
      Mab35
      LOVO
      42
      InterferonEnhanced blood flow83% increase in uptake 1.5 h after administrationMEM136
      WM-9
      43
      Interleukin 2 conjugateEnhanced vasopermeability275% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      TNF-alpha conjugateEnhanced vasopermeability and blood flow213% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      Interleukin 1 conjugateEnhanced vasopermeability and blood flow200% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      Leukotriene-B4 conjugateEnhanced blood flow122% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      Histamine conjugateEnhanced vasopermeability118% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      Physalaemin conjugateEnhanced blood flow71% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      Bradykinin conjugateEnhanced blood flow23% increase in uptake 3 days after administrationTNT-1 F(ab′)2
      ME-180
      45
      PEP2-Ab conjugateEnhanced vasopermeability249% increase in uptake 3 days after administrationB72.3
      LS174T
      46
      A22p-Ab conjugateEnhanced vasopermeability50%–100% increase in uptake at 3 and 12 h after administrationCetuximab/A459
      Trastuzumab/SKOV3
      49
      iRGDEnhanced vasopermeabiltiy3,900% Increase at 3 h by ELISATrastuzumab
      BT-474
      48
      Mannitol InfusionOsmotic opening of BBB234% and 32% increase in F(ab′)2 and mAb AUC (0.5–72 h)P1.17
      LX-1 SCLC
      58
      Focused ultrasoundTransient disruption of BBB5,577% increase in uptake 2 h after administrationBevacizumab
      U87 glioma
      63
      Angiopep-2-Ab conjugateRMT through BBB by LRP1 binding˜300% increase in tumor uptake 24 h after administrationTrastuzumab
      BT-474
      68
      Human melanotransferrin-Ab conjugateRMT through BBB by LRP1 binding415% increase in tumor uptake 2 h after administrationTrastuzumab
      MDA-MB-231-BRHER2/eGFP
      69
      • View popup
      Table 3

      Extracellular matrix modulation approaches

      TreatmentImpact on tumorImpact on mAb tumor PKmAb/tumor modelSource
      Intratumoral collagenaseCollagen degradation80%–100% increase in diffusion 24 h after collagenase injectionNon-specific IgG (S1)
      HSTS-26T and U87
      77
      Intravenous collagenaseCollagen degradation/decrease in tumor interstitial fluid pressure90%–140% increase in uptake at 24 hTP-3
      OHS
      79
      Relaxin infusionDownregulation of tumor fibrosis/decrease collagen fiber length and signal80% increase in diffusion coefficient after a 12-day relaxin infusionNon-specific IgG
      HSTS-26T
      78
      Intratumoral injection of bovine hyaluronidaseHyaluronan degradation/decrease in interstitial fluid pressure70% increase in uptake 9 days after administrationTP-3
      OHS
      80
      Pegylated human hyaluronidase (PEGPH20)Tumor hyaluronan degradation100% increase in uptake 2 days after administrationTrastuzumab
      SKOV3-HAS2
      82
      Pulsed ultrasoundStructural modification of extracellular matrix and widening of intercellular gaps36% Increase in tumor AUC (0–5 days)MX-B3
      A431
      130
      • View popup
      Table 4

      Antigen and cellular modulation approaches

      ApproachImpact on mAb tumor PKmAb/tumor modelSource
      pH sensitive mAb30% increase in tumor AUC (0–14 days) in comparison to non-pH sensitive mAb T84.6610H6/T84.66
      MC38CEA+
      126
      Paclitaxel administered 2 days after mAb administration30% increase in cumulated activity 0–6 days111In-DOTA-Gly3Phe-m170/breast or prostate cancer106
      5-fluorouracil treatment 2 days prior to mAb administration148% increase in uptake 5 days after administration125I-NHS76
      Colon 26
      107
      Paclitaxel treatment 2 days prior to mAb administration102% increase in uptake 5 days after administration125I-NHS76
      Colon 26
      107
      Tofacitinib48% increase (LMB) and 133% increase (BV421) in tumor cell uptake/binding 3 h after administrationLMB-100/KLM-1
      BV421/MDA-MB-461
      108
      Junction opener 1500% increase in tumor uptake 12 h after administrationTrastuzumab
      HCC1954
      109
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    Strategies to enhance monoclonal antibody uptake and distribution in solid tumors
    Brandon M. Bordeau, Joseph P. Balthasar
    Cancer Biology & Medicine Aug 2021, 18 (3) 649-664; DOI: 10.20892/j.issn.2095-3941.2020.0704

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    Strategies to enhance monoclonal antibody uptake and distribution in solid tumors
    Brandon M. Bordeau, Joseph P. Balthasar
    Cancer Biology & Medicine Aug 2021, 18 (3) 649-664; DOI: 10.20892/j.issn.2095-3941.2020.0704
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