وابستگی توزیع زیستی آنتی بادی ضد CD66 در تفکیک مقدار ثابت: یک مطالعه شبیه سازی

In radioimmunotherapy (RIT) with radiolabelled anti-CD66 antibody, the red bone marrow is selectively irradiated. A preceding study, employing a physiologically based pharmacokinetic model, has shown that currently about 50% of the anti-CD66 antibody is accumulated in the red marrow. In this work, the potential improvement of the biodistribution is quantified for other anti-CD66 antibodies with lower dissociation constants KD. Biodistribution simulations were performed based on a recently published mathematical model for a 10- and 100-fold lower monovalent KD. The therapeutic index was compared to the therapeutic index which is achieved using the actual antibody. The simulations indicate that a considerably increased therapeutic index can be obtained by decreasing the dissociation constant.A reduction of the KD to 10-fold or 100-fold lower values would lead to an improvement of the therapeutic index, by a factor of 2.4-5 and 2.4-6.5 respectively. To investigate the predicted improvement of the radioimmunotherapy, new anti-CD66 antibodies with lower dissociation constants should be developed.

Radioimmunotherapy (RIT) with 90Y-labelled anti-CD66 antibody is used to selectively deliver radiation to the red bone marrow [1], [2] and [3]. Pretherapeutic measurements of the 111In-labelled anti-CD66 antibody biodistribution have shown that about 50% of the antibody accumulates in the red bone marrow [4]. The modelling of RIT with anti-CD66 antibody indicates a potential improvement using smaller amounts of antibody for therapy [4]. A further approach to increase the red marrow uptake of the labelled antibody might be using an antibody directed against the same antigen with a lower dissociation constant KD. Thomas et al. have demonstrated using computer simulations that (for the proper antibody dose and antigen distribution) a decreasing KD leads to a higher therapeutic index, i.e. a higher ratio of absorbed doses in solid tumour versus normal tissue [5]. Thus, the development of a novel antibody with a reduced dissociation constant might increase the therapeutic index and therefore enhance the effectiveness and efficiency of the therapy. Here, the benefit of a novel anti-CD66 antibody with a lower KD was quantified. Computer simulations were conducted using a recently published anti-CD66 antibody physiologically based pharmacokinetic (PBPK) model [4]. The ratios of the residence times for the red marrow and liver were computed for a 10- and 100-fold lower monovalent KD and the potential improvement compared to the currently used antibody were calculated.

In this work, a recently published PBPK model, describing the biodistribution of 111In-labelled anti-CD66 antibody [4], was employed to investigate the influence of using anti-CD66 antibodies with lower dissociation constants on its accumulation in the red marrow, liver and spleen. In the previous study, the model was fitted to biokinetic data and the number of antigens in the red marrow was estimated being in the range of the given amount of antibodies [4]. Thus, the value of KD is relevant for the fraction of antibody that binds [5]. Based on these findings biodistribution simulations were conducted for antibodies with an assumed 10- and 100-fold lower KD. The simulations suggest a considerable improvement would be achievable using a lower KD antibody. Higher selectivity allows smaller injected activities to achieve the same absorbed dose in the red marrow and thus leads to less toxicity in normal tissue. Moreover, concurrently a smaller amount of antibody mass is required for a given specific activity. This further improves biodistribution [4] and additionally reduces adverse effects. For example, a reduction of injected activity to about 73% would give the same absorbed dose in bone marrow for a KD smaller by a factor of 10 (Table 1). As the residence time for liver is reduced to about 44% in this case, the absorbed dose is reduced in total by a factor of 0.73 × 0.44 = 0.32. Here, KD is a monovalent dissociation constant, determined by fitting biodistribution data of the blood and organs to a PBPK model. In the literature similar values (KD = 40 nM) are reported [10]. The bivalent dissociation constant is assumed to be directly proportional [8]. Comparisons to experimentally observed [11] values are thus difficult and might be misleading. Nevertheless, for this antibody an observed dissociation constant of 5·10-10 M was determined [12]. Antibodies have observed KD values in the range 10-8 M to 10-12 M. This implies that a reduction of the KD should be possible in principle using state of the art antibody developing methods [13]. In conclusion, the results indicate that the development of an antibody with a lower dissociation constant could substantially improve RIT with anti-CD66 antibody, as it considerably increases the therapeutic index