PTH1R Antibodies as Negative Modulators for Hypercalcemia Treatment
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Solution Overview
Problem
Current treatments for conditions associated with increased parathyroid hormone or parathyroid hormone-related protein expression, such as hypercalcemia and hyperparathyroidism, are limited in efficacy and specificity, particularly in addressing the underlying receptor-mediated signaling pathways.
Innovation Solution
Development of antibodies specifically targeting the parathyroid hormone receptor 1 (PTH1R) with high affinity, capable of binding to the N-terminal portion and acting as negative modulators to weaken the interaction between PTH or PTHrP and PTH1R, thereby inhibiting calcium flux and cAMP accumulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for hypercalcemia and hyperparathyroidism, then treatment can be provided, but efficacy and specificity are limited
Solution Approach 1:
The patent extracts and targets the specific PTH1R receptor as the therapeutic focus, separating the treatment mechanism from conventional non-specific approaches. By isolating the receptor-level interaction, the antibody therapy achieves high specificity for PTH1R-mediated signaling pathways, thereby improving treatment efficacy while maintaining targeted precision.
Solution Approach 2:
The PTH1R antibody acts as an intermediary substance that mediates the interaction between PTH/PTHrP and the PTH1R receptor. This intermediary blocks the harmful signaling pathway at the receptor level, providing both high efficacy in suppressing hypercalcemia and high specificity in targeting the PTH1R pathway, thus resolving the contradiction between treatment effectiveness and targeting precision.
2Measurement precision
If PTH1R antibodies with high affinity are developed, then binding affinity improves, but manufacturing and development complexity increases
Solution Approach 1:
The patent applies parameter changes by optimizing the antibody's binding affinity parameters (Kd values of 10^-6 M or less) to achieve high precision in PTH1R binding. By carefully controlling and adjusting these affinity parameters during antibody development, the patent achieves the desired measurement precision while managing the complexity of the development process through systematic parameter optimization.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies effectively reduce hypercalcemia and hyperparathyroidism symptoms by specifically targeting PTH1R, providing a more precise and potent therapeutic approach compared to existing treatments.
Implementation Method 1
The disclosure provides antibodies that bind PTH1R. In particular, the present disclosure provides methods of use of such antibodies in the treatment of cancer, Humoral Hypercalcemia of Malignancy (HHM), Primary Hyperparathyroidism (PHPT), Secondary Hyperparathyroidism (SHPT) and cachexia.
Implementation Method 2
In a preferred embodiment, the antibody is a negative modulator antibody, optionally wherein the antibody is capable of weakening the binding affinity between PTH or PTHrP and with PTH1R by at least about 2-fold, optionally up to 1000-fold.
Implementation Method 3
In various embodiments, the antibody inhibits calcium flux in a cell in response to stimulation of the receptor with parathyroid hormone (PTH) or parathyroid hormone related protein (PTHrP).
Implementation Method 4
In related embodiments, the antibody inhibits PTH- or PTHrP-mediated cyclic adenosine mono-phosphate (cAMP) accumulation.
Data Source
AI summary
The present disclosure relates, in general, human antibodies against human parathyroid hormone receptor 1 (PTH1R) and methods of use of such antibodies in the treatment of cancer, Humoral Hypercalcemia of Malignancy (HHM), or Primary Hyperparathyroidism (PHPT) and Secondary Hyperparathyroidism (SHPT) and cachexia.