The Crucial Role of HLA Typing in Donor Selection for Cell and Gene Therapies
The Human Leukocyte Antigens (HLA) are surface proteins on our cells and tissues serving as a mechanism for the body to distinguish between self and non-self, so our immune system can activate an appropriate immune response against invading pathogens such as bacteria, viruses, and parasites. HLA is the human form of major histocompatibility complex (MHC), which is divided into three major classes: I, II, and III (Figure 1). Class I and II MHC molecules are directly involved in antigen presentation, while the class III MHC molecules are involved in other immune-related functions, such as inflammation and protection against stress and damage. HLA genes are hugely diverse, with more than 30,000 different HLA alleles reported—the multitude of HLA markers makes HLA typing much more complex than blood typing.
Clinically, the most common reason to perform HLA typing is to select donors who can provide the safest tissue transplants (solid organ or hematopoietic stem cell transplantation). A key challenge is that certain HLA types are present in higher frequency in specific ethnic groups, which means some patients can face a greater challenge in finding a good HLA match because they are under-represented in bone marrow registries. Researchers also use HLA data in a range of drug development applications to minimize the potential of transplant rejection or other serious complications such as graft versus host disease (GVHD) in order to create safe and efficacious therapies.
HLA Typing in Cell and Gene Therapies
In the development of allogeneic cell and gene therapies (CGTs), knowing the HLA genotype of donors is critical to ensure the success and safety of these treatments. It can help to identify potential issues with compatibility and allow for personalized treatments that are tailored to the individual patient’s needs. Research suggests that a donor must match a minimum of 6 HLA markers to be a good match. The level of HLA mismatches correlates with the strength of the immune system response. Based on this knowledge, HLA typing is used not only for matching a donor and a recipient but also to estimate the immunological risk of donor recognition.
While it’s not possible to get a perfect HLA match in an allogeneic setting for every patient, HLA genotyping can aid in patient selection during optimization of a therapy to find individuals with common HLA types in hopes of minimizing host-versus-graft disease and other alloreactivities as much as possible in a larger patient population. Conversely, the information can help avoid mismatches that could result in less optimal patient outcomes. High-resolution HLA technologies, such as next-generation sequencing (NGS), can provide more detailed HLA allele information than conventional serological methods and DNA-based HLA typing using PCR. NGS enables high-throughput, high-resolution, and accurate sequencing of DNA, making it an ideal technology for HLA typing. Additionally, the value of a diverse and highly characterized donor pool should not be understated since the ability to find the individual donors who have the desired HLA type for a specific cell and gene therapy program is critical to development.
AllCells’ HLA-Typed Donor Pool
Our CGT clients have access to tens of thousands of well-characterized, HLA-typed, highly engaged recallable donors from AllCells-LeukoLab collection sites across the US. AllCells’ Donor Management System (DMS) contains all the critical donor attribute information of qualified donors within a single repository, enabling our team of experts to use the proprietary DMS software to help clients navigate donor requirements based on timeline, risk, and cost considerations for their specific CGT program.
Importantly, the DMS software has a real-time HLA dashboard and reporting system that can be mined by the DMS team to rapidly identify relevant donors by HLA type based on specific demographic requirements. This includes (but is not limited to) donor gender, age, CMV status, BMI, race, blood type, and eligibility status for various products (i.e., mobilized or clinical grade collections). Figure 2 shows a snapshot of a subset of donors with a relatively common HLA type (A*02:01) segmented by blood type and CMV status.
AllCells’ diverse donor network also contains less common HLA types such as B*07:02 that can also be segmented by donor demographic and many unique HLA alleles are represented, which is advantageous for developers seeking specific donor attributes that represent certain patient populations in CGT development as shown in Figure 3.
AllCells takes a consultative approach with every client to understand specific program requirements with respect to donor attributes, screening needs, collection cadence requirements or timeline restrictions. Our multidisciplinary Donor Management team can create customized recruitment solutions to ensure a high conversion rate from donor identification to successful collection by utilizing the DMS and building upon relationships we have curated with our individual donors. Clients can access allogeneic donors who are reliable and recallable for repeat apheresis collections to mitigate risk and ensure a dependable supply chain. We have partnered with leading biopharmaceutical companies using this approach to meet both short- and long-term projects across all stages of the product lifecycle – from inception to commercial manufacturing with success.