The effects of clinically relevant hyperthermic temperatures on the kinetic binding parameters of a monoclonal antibody

Hauck, Marlene; Dewhirst, Mark W.; Zalutsky, Michael R.

doi:10.1016/0969-8051(96)00039-x

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…assessed the effects of temperature over a range of 1–37°C and reported a 2‐ to 18‐fold increase in the association rate and a 20‐ to 50‐fold increase in the dissociation rate of antibodies to and from murine cell surface antigens, respectively . However, the temperature range used for mild hyperthermia, that is, heating from a baseline of 37–45°C, did not affect the association or dissociation rates of the mAb binding . We now understand that altering the interaction kinetics of mAbs does not play a role in the hyperthermia‐induced enhancement of mAb targeting to cancer cells.…”

Section: Discussionmentioning

confidence: 94%

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

et al. 2016

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Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.

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Section: Discussionmentioning

confidence: 94%

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

et al. 2016

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“…Because ch8lC6 recognizes an extracellular matrix protein, tenascin, this may decrease the likelihood that hyperthermia modulated its expression; nonetheless, shedding might occur. Finally, hyperthermia might alter the kinetics of MAb-antigen interaction; however, we have demonstrated that the binding kinetics of 81 C6 to tenascin are the same over a temperature range of 37-450C (Hauck et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The lower molecular weight and avidity of the Fab should facilitate its diffusion into inner spheroid regions; however, it is the outer regions of the spheroid in which blocking of labelled MAb binding is required. In addition, because the affinity of 8 1C6 Fab is more than tenfold lower than intact MAb (Hauck et al, 1996), Fab bound to the outer spheroid layers would be a poor competitor for subsequently administered labelled intact MAb. Essand and colleagues (1995a,b) have demonstrated that increased penetration of labelled MAb into spheroids could be accomplished by previous administration of cold MAb.…”

Section: Discussionmentioning

confidence: 99%

“…This is consistent with observations of higher penetration of MAb into tumour spheroids with lower affinity MAbs or lower antigen concentrations (McFadden and Kwok, 1988;Langmuir et al, 1992b). Because ch8lC6 has a high affinity for tenascin (KA approximately 1.4 x 109 M-1) (Hauck et al, 1996), the binding site barrier may have impeded its penetration with the D-247 MG tenascin-positive spheroids. Hyperthermia did not exacerbate this barrier to penetration as increasing the incubation temperature from 37°C to 42°C does not have a significant effect on the association or disassociation rate constants, or the equilibrium constant for the binding of radioiodinated 81C6 to D-247 MG glioma cells in vitro (Hauck et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxicity of α-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia

Hauck

Larsen²,

Welsh³

et al. 1998

Br J Cancer

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Summary The high linear energy transfer, a-particle-emitting radionuclide astatine-211 (21'At) is of interest for certain therapeutic applications; however, because of the 55-to 70-jim path length of its a-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of a-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 21'At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 gm) greater than the range of 21'At a-particles. Hyperthermia for 1 h at 420C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml-'. A significant regrowth delay was observed at 125 and 250 kBq ml-' in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 420C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids.Keywords: monoclonal antibody; hyperthermia; spheroid; astatine-21 1; a-emitterThe use of a-particle-emitting radionuclides for endoradiotherapy has several potential advantages compared with 1-emitters. The high linear energy transfer (LET) of a-particles makes them highly cytotoxic, rendering even hypoxic cells vulnerable. In addition, a-particles have relatively short effective path lengths in tissue, decreasing the radiation delivered to normal tissues located in close proximity to the tumour. For example, the mean path length of the a-particles emitted by 7.2-h half-life 21'At is 55-70 gm compared with 800 gm for the 5-particles emitted by '3'I (Gaze et al, 1992;. In contrast, the short a-particle range is potentially problematic because of the necessity for achieving homogeneous distribution of the radionuclide in the tumour for effective therapy. The limited range of a-particles has led investigators to focus therapeutic applications in which the tumour is present in thin sheets, such as neoplastic meningitis and peritoneal metastasis. The efficacy of 21'At-labelled monoclonal antibodies (MAbs) in a rat model of neoplastic meningitis has been encouraging .Micrometastatic disease could offer another potential application of a-emitters if sufficiently homogeneous tracer distribution could be achieved. The determination of the most appropriate radionuclide for the treatment of small volume disease has been the focus of both experimental and theoretical studies (Humm and Cobb, 1990;Langmuir et al, 1990; 1992a higher absorbed dose fraction within the tumour compared with long-range 3-emitters such as 90Y, particularly for lesions of less than...

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“…Hyperthermia is the treatment of malignant diseases by the application of heat. Clinically relevant hyperthermic temperature range is between 40 and 43 • C [2,4]. Hyperthermia itself has been shown to be cytotoxic and several chemotherapeutic agents in combination with hyperthermia have shown additive cytotoxic effects [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Effect of temperature on surface properties of cervical tissue homogenate and organic phase monolayers

Preetha

Banerjee

Huilgol

2007

Colloids and Surfaces B: Biointerfaces

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The effects of clinically relevant hyperthermic temperatures on the kinetic binding parameters of a monoclonal antibody

Cited by 7 publications

References 19 publications

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Cytotoxicity of α-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia

Effect of temperature on surface properties of cervical tissue homogenate and organic phase monolayers

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